Effects of peripheral administration of a Neuromedin U receptor 2-selective agonist on food intake and body weight in obese mice.

BACKGROUND: Neuromedin U (NMU) is a neuropeptide with various physiological functions, including regulation of smooth-muscle contraction, blood pressure, stress responses and feeding behaviors. NMU activates two distinct receptors, NMUR1 and NMUR2, which are predominantly expressed in peripheral tissues and the central nervous system (CNS), respectively. It is reported that the NMU signaling system regulates food intake (FI) and body weight (BW) via NMUR2, suggesting that an NMUR2 agonist exhibiting anorectic effects would be a potential therapy for obesity. METHODS: Antiobesity effects of NMUR2 activation were assessed using a recently developed, novel NMUR2-selective agonist, NMU-7005 (a polyethylene glycolated octapeptide). Here we assessed cumulative FI and BW loss after peripheral administration of NMU-7005 in NMUR2 knockout and diet-induced obese mice. To gain mechanistic insights, we performed immunohistochemical analysis of c-Fos-like protein expression in the brain. RESULTS: We found that NMU-7005 was a NMUR2-selective agonist with little activity toward NMUR1. The anorectic effect of NMU-7005 was completely abrogated in NMUR2 knockout mice. Repeated subcutaneous administration of NMU-7005 showed a potent antiobesity effect with FI inhibition (P<0.025) in diet-induced obese mice. NMU-7005 in combination with the glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide showed an additive antiobesity effect, suggesting that NMUR2-mediated anorectic action is different from that of GLP-1R agonists. NMU-7005 also elicited a minimal conditioned taste-aversive effect, while the effect of liraglutide was significant. As c-Fos expression was upregulated in the hypothalamus and the medulla oblongata in NMU-7005-administered mice, the pharmacological effects of NMU-7005 appeared to be mediated via activation of the CNS. CONCLUSION: Our results demonstrated that a novel NMUR2-selective agonist, NMU-7005, is a beneficial tool for the elucidation of NMUR2-mediated physiological functions, which is a promising therapeutic strategy for treating obesity.

Visit-to-visit blood pressure variability, average BP level and carotid arterial stiffness in the elderly: a prospective study.

In a cross-sectional study, visit-to-visit blood pressure (BP) variability was shown to be associated with artery remodelling. Here, we investigated the impact of visit-to-visit BP variability and average BP on the carotid artery remodelling progression in high-risk elderly according to different classes of antihypertension medication use/non-use. BP measurements and carotid ultrasound were performed in the common carotid artery in 164 subjects (mean age 79.7 years at baseline, 74.7% females) with one or more cardiovascular risk factors. Based on 12 visits (1 × /month for 1 year), we calculated visit-to-visit BP variability expressed as the standard deviation (s.d.), coefficient of variation (CV), maximum BP, minimum BP and delta (maximum-minimum) BP. We measured mean intima-media thickness (IMT) as well as stiffness parameter ß were measured at baseline and at the mean 4.2-year follow-up. In a multiple regression analysis, the maximum, minimum, s.d. and average of systolic BP (SBP) were significantly associated with a change in ß-values between the baseline and follow-up after adjustment for age, smoking, lower high-density lipoprotein level, baseline ß-value and follow-up period. There were no significant associations between the visit-to-visit BP variability measures and the change in mean IMT. Significant associations of maximum, minimum, s.d. and average SBP were found with increased ß-values in the subjects without calcium channel blocker (CCB) use and in the subjects using renin-angiotensin system inhibitors (RASIs). Thus, exaggerated visit-to-visit SBP variability and a high average SBP level were significant predictors of progression in carotid arterial stiffness in high-risk elderly without CCBs use and in those using a RASI.

MRI findings of mucoepidermoid carcinoma of the parotid gland: correlation with pathological features.

OBJECTIVE: The aim of this study was to correlate the MRI appearance and pathological findings in each grade of the mucoepidermoid carcinoma (MEC) of the parotid gland. METHODS: We reviewed surgically proven MECs of parotid glands in 20 patients. Pathologically, 5 tumours were high-grade, 3 were intermediate and 12 were low-grade. MR images were evaluated with emphasis on signal intensities on T(2) weighted images, margin characteristics and lymph node metastasis, correlating these with pathological features. RESULTS: Among the high-grade MECs, four out of five tumours showed inhomogeneous low to intermediate signal intensity on T(2) weighted images, reflecting high cellularity. All tumours had an ill-defined margin, reflecting invasive tumour growth. Among the intermediate-grade MECs, all three tumours showed intermediate signal intensity on T(2) weighted images and two tumours had an ill-defined margin. Among the low-grade MECs, 11 of the 12 tumours had a hyperintense area on T(2) weighted images because of the existence of abundant mucin secreting cells. Seven tumours had an ill-defined margin, reflecting peritumoural inflammatory changes rather than invasive tumour growth. Lymph node metastasis was seen in three high-grade MECs. CONCLUSION: MECs of the parotid gland show variable MRI findings reflecting their histological nature, which seems to have certain tendencies depending on the tumour grade.

Myocardial performance index for assessment of left ventricular outcome in successfully recanalised anterior myocardial infarction.

OBJECTIVE: To investigate whether the myocardial performance index (MPI) can predict left ventricular functional outcome in patients with early recanalisation after anterior acute myocardial infarction (MI) and to determine when the index should be measured. DESIGN: MPI was measured serially by two dimensional Doppler echocardiography after successful percutaneous coronary intervention (PCI). Left ventricular function was evaluated by echocardiography and left ventriculography. To assess coronary microvascular damage, the coronary flow velocity pattern was measured immediately after PCI with a Doppler guidewire. SETTING: Hiroshima City Asa Hospital. PATIENTS: 32 consecutive patients with their first anterior acute MI who had complete occlusion of left anterior descending coronary artery. INTERVENTIONS: Successful PCI within six hours of symptom onset. MAIN OUTCOME MEASURES: Left ventricular anterior wall motion score index (A-WMSI), left ventricular end diastolic pressure (LVEDP), left ventricular ejection fraction (LVEF), and left ventricular end diastolic volume (LVEDV). RESULTS: There was a significant negative correlation between MPI on day 2 and the coronary diastolic deceleration time (r = -0.66, p < 0.002), as well as a significant positive correlation with the coronary diastolic deceleration rate (r = 0.74, p < 0.0001). MPI on day 2 was significantly correlated with the short and long term changes of A-WMSI and with the short term changes of LVEDP. Furthermore, MPI on day 2 was significantly correlated with the short and long term changes of LVEF (r = -0.52, p < 0.003, and r = -0.64, p < 0.0008, respectively) and of LVEDV (r = 0.51, p < 0.003, and r = 0.41, p < 0.05, respectively). CONCLUSIONS: Doppler derived MPI on day 2, representative of the early coronary microvascular state, can predict the left ventricular functional outcome after early successful recanalisation of a patient's first anterior acute MI.

New pain following cordotomy: clinical features, mechanisms, and clinical importance.

OBJECT: The clinical features, possible causes, and contributing factors associated with novel spontaneous pain following unilateral cordotomy were investigated to clarify the mechanism and clinical importance of this pain. METHODS: Forty-five patients who underwent cordotomy for severe unilateral cancer pain were included in this study. New pain occurred in 33 (73.3%) of 45 patients. Pathological conditions of tissue demonstrated on imaging corresponded to new pain in eight patients, referred pain in five, and neither of these in 15 patients. New pain was centered opposite the site of the original pain in a mirror-image location in 28 patients and rostral to the original pain in five patients. It was temporary in seven patients, weaker than the original pain in 25, and as severe as the original pain in one patient. The incidence of moderate or severe pain was significantly higher in patients with confirmed tissue disease (six of eight patients) than in those without (six of 20 patients). An important contributing factor to the occurrence of new pain was the achievement of analgesia by performing the cordotomy. CONCLUSIONS: The present results indicate that new pain occurs frequently after unilateral cordotomy. Nonetheless, cordotomy may still be indicated for unilateral uncontrollable pain because new pain, when present, was weaker and more easily controlled than the original pain in nearly all cases. The authors speculate that new pain may represent a type of referred pain from the original painful area or may arise from sensitization of contralateral spinal nociceptive circuits due to metastasis or tumor infiltration, and that new pain is potentiated by the interruption of descending inhibitory pathways.

Biological functions of extravasated serum IgG in rat brain.

During blood-brain barrier opening serum IgG could be extravasated. The function of intraparenchymal IgG, however, is unknown. Its biological effects in the acute phase were currently investigated. From rat autoserum IgG was purified and injected into the cortex. Similarly, IgG-Fab fragment was prepared and administered likewise. As for the control group, only vehicle was injected. Animals were sacrificed on days 1, 2 and 4 after the infusion and were histologically evaluated. On days 1 and 2, the infusion of IgG caused significant intraparenchymal infiltration of neutrophils which expressed LFA-1-alpha. It also induced CR3 up-regulation in microglia and endothelial ICAM-1 expression. On day 4, these findings had disappeared. HE stained brain sections and the TUNEL method did not reveal significant nerve cell death in IgG injected animals during the experiment as compared to the controls. IgG-Fab did not cause significant changes either. Extravasated IgG has been viewed to have biochemical functions. Its Fc fragment seemed to cause microglial and endothelial activation, followed by leukocytic infiltration. This sequence itself was not neurotoxic. Therefore, it is suggested that extravasated IgG is one of the inducers that modulate cellular responses in the acute phase of brain damage.

Ischemic preconditioning suppresses the noradrenaline turnover in the rat heart.

OBJECTIVE: The mechanism by which ischemic preconditioning protects the heart is presumed to be related to the reduction of energy consumption during a subsequent myocardial infarction. Since the sympathetic nervous system enhances cardiac function and energy consumption, we investigated the relation between ischemic preconditioning and the turnover rate of noradrenaline (NA) in the rat heart. METHODS: The effect of 3 cycles of 5-min occlusions of the rat left coronary artery on changes in arterial blood pressure and heart rate provoked by a subsequent 30 min of ischemia were examined until 60 min after reperfusion. The effect of 3 cycles of occlusions on the infarct size was also evaluated 60 min after reperfusion by comparing the infarcted area with the area at risk in these animals (6 per preconditioned and sham-operated group). The tissue concentration of NA during sustained ischemia was determined in the left ventricle, the intraventricular septum, and the right ventricle in the preconditioned and sham-operated groups. Changes in the turnover rate of NA after 3 cycles of occlusions were also evaluated by assessing the alpha-methyl-p-tyrosine-induced depletion of NA (n = 7 per group). RESULTS: A series of transient occlusions reduced the infarct size 60 min after a sustained ischemia for 30 min. Arterial pressure and heart rate were not affected. The concentration of NA was decreased in the left ventricle 60 min after the onset of sustained ischemia in both the preconditioned and sham-operated groups. The treatment with alpha-methyl-p-tyrosine decreased the NA concentration in all regions of the heart in the sham-operated group after 60 min. However, the treatment with alpha-methyl-p-tyrosine did not deplete the NA concentration in both the occluded and nonoccluded regions in the preconditioned group. CONCLUSIONS: Transient ischemia ameliorated the heart injury induced by a subsequent sustained ischemia, as assessed histologically. The activity of the sympathetic nervous system in all regions of the heart was reduced by transient ischemia in the left coronary vascular bed. These findings suggest that the inhibition of the sympathetic nervous system by the treatment of ischemic preconditioning takes part in the cardiac protection.

Hypothermia increases the threshold for ischemic preconditioning.

OBJECTIVES: Both hypothermia and ischemic preconditioning are known to provide tolerance to myocardial ischemia and reperfusion. The aim of this study was to determine whether hypothermia during the ischemic preconditioning period attenuates the protective effect of ischemic preconditioning. METHODS: Experiments were performed in buffer-perfused isolated rabbit hearts. All hearts underwent 45 minutes of regional ischemia, followed by 2 hours of reperfusion. Ischemic preconditioning was elicited by either one or four periods of 5 minutes of regional ischemia. Hypothermia (25 degrees C) was induced beginning either 20 or 50 minutes before the 45-minute period of regional ischemia; normothermia (38 degrees C) was restored 10 minutes before the 45-minute period of regional ischemia. Except for the hypothermic periods noted, hearts were maintained at 38 degrees C. RESULTS: Normothermic ischemic preconditioning with either one or four cycles of 5 minutes of coronary occlusion resulted in a profound reduction of infarct size (58% reduction with one cycle, p < 0.05; 95% reduction with four cycles, p < 0.01). Hypothermic ischemic preconditioning with one cycle of 5-minute coronary occlusion resulted in no reduction of infarct size but hypothermic ischemic preconditioning with four cycles of 5-minute coronary occlusions resulted in a 94% reduction of infarct size (p < 0.01). Myocardial glycogen and lactate levels were maintained near control levels during hypothermic ischemia. CONCLUSIONS: From these data we conclude that hypothermia during the preconditioning period increases the threshold for eliciting the infarct limitation of ischemic preconditioning.

[Percutaneous drainage of a bulla with tuberculous infection in a patient].

A 63-year-old man complaining of low grade fever and dry cough was admitted to our hospital. Chest X-ray showed infiltrative shadows and a bulla with a fluid level in the left upper lung field. Bacteriological examination of sputum and bronchoalveolar lavage fluid did not yield any diagnostic results. Percutaneous aspiration of the bulla under fluoroscopy was performed. Bulla with tuberculous infection was considered because a high ADA level was detected in the fluid of the bulla. A culture of the bulla fluid was positive for mycobacterium tuberculosis (TB), which was sensitive to all anti-mycobacterial drugs. The fluid in the bulla gradually increased, and occupied the entire space of the bulla three months later. Percutaneous aspiration of the bulla was performed again and a fluid smear was positive for TB. It was thought that systemic administration of anti-mycobacterial drugs had been ineffective, so percutaneous drainage and subsequent injection of anti-mycobacterial drugs into the bulla was performed. The fluid in the bulla subsequently disappeared and the bulla shrank gradually. Percutaneous drainage of a bulla with tuberculous infection should be considered in those who do not respond to medical management.

[Clinical characteristics of pulmonary embolism without definitive predisposing factors].

Patients with pulmonary embolism may have no definitive predisposing factors for thrombi. The clinical entity of chronic pulmonary embolism is also uncertain. This study clarified the clinical characteristics of pulmonary embolism without definitive predisposing factors. During the last 10 years, 36 consecutive patients were diagnosed as having pulmonary embolism (mean age 61 years, female 75%). Twenty-four patients (67%) had definitive predisposing factors ("definitive" group). Patients without definitive predisposing factors had the following characteristics. The onset of symptoms was out-hospital and insidious. The main symptom was exertional dyspnea without acute episode compatible with an embolism. In four patients (33%) there was a delay of over 2 years form the onset of symptoms to the diagnosis. Three patients had been treated for depression. Thrombolytic therapy caused an inadequate fall in mean pulmonary artery pressure from 41 +/- 11 to 24 +/- 8 mmHg and in three patients it remained over 30 mmHg. Deep vein thrombosis were found in four of nine patients in whom venography were performed 10 days after thrombolytic therapy, but only one patient showed thrombus in the "definitive" group. During the convalescent stage, all patients were treated with prophylactic warfarin. Home oxygen therapy was indicated in three patients and an inferior vena caval filter was implanted in two patients. One third of patients with pulmonary embolism in our institute had no definitive predisposing factors. In these patients, even with thrombolytic therapy, recovery of pulmonary hypertension was often insufficient and deep vein thrombosis persisted. Clinicians should be aware of this disease to avoid undue delay in its diagnosis.

[Two cases of tubercle bacilli infected pulmonary bulla].

Two cases of tubercle bacilli infected bulla are reported. Case 1; A 78-year-old man visited our hospital complaining of fever and chest pain. The chest radiograph revealed the bulla with air fluid level in the left upper lung field. Mycobacterium tuberculosis was detected in the fluid obtained by percutaneous lung aspiration. He was treated with anti-mycobacterial drugs and showed improvement. Case 2; A 66-year-old man visited our hospital complaining of fever, chest pain and dry cough. The chest radiograph revealed the bulla with air fluid level in the left upper lung field. A diagnosis of tubercle bacilli infected bulla was considered because of high level of ADA in the fluid obtained by percutaneous lung aspiration, and anti-mycobacterial drugs were administered. His symptoms were improved and the frequent chest radiograph showed gradual absorption of the fluid. It is suggested that ADA and bacteriological examinations of the fluid obtained by percutaneous lung aspiration are useful for early diagnosis of tubercle bacilli infected bulla.

[Predictors for the massive thrombi occurring in the right coronary artery related to acute myocardial infarction].

Acute myocardial infarction (AMI) related to the right coronary artery (RCA) is associated with a lower reperfusion rate and higher reocclusion rate in the acute phase than AMI related to the left coronary artery. The greater susceptibility of the RCA to development of large thrombi makes successful reperfusion more difficult to achieve. This study investigated predictive factors for massive thrombus in the RCA before the selection of the treatment to achieve better rates of reperfusion. We classified 51 patients with AMI related to RCA into the massive (linear intraluminal radiolucency > 3 cm) thrombus group (9 patients) and the non-massive thrombus group (42 patients). 1) HISTORY: Patients in the massive thrombus group had a greater incidence of hypertension than the non-massive thrombus group, with more left ventricular hypertrophy (p < 0.05). There were no significant differences in other coronary risk factors. 2) RCA morphology: The maximum RCA diameter was significantly greater in the massive thrombus group than that in the non-massive thrombus group [proximal to the right ventricular branch, 4.2 vs 3.2 mm (median); distal to the right ventricular branch, 4.2 vs 3.4 mm, p < 0.05]. 3) Conditions of onset: The elapsed time was significantly longer in the massive thrombus group (15 hours) than that in the non-massive thrombus group (2.5 hours, p < 0.05). More massive thrombus cases were observed in summer (p < 0.05), but there was no evident correlation between massive thrombus formation and the onset time of day, weather, Hct and coagulation factor at the onset, left ventricular ejection fraction or left ventricular end-diastolic pressure.(ABSTRACT TRUNCATED AT 250 WORDS)