Selective antagonism of the NPY Y5 receptor does not have a major effect on feeding in rats

Neuropeptide Y (NPY) is thought to play a key role in stimulating feeding, thus making NPY receptors attractive appetite suppressant drug targets for treating obesity. Because the orexigenic effects of NPY have been ascribed to actions at the NPY Y5 receptor, we have determined the role of this receptor in feeding in rats, using a small molecule antagonist of this receptor. NPY5RA-972 is a selective and potent (<10 nmol/l) NPY Y5 receptor antagonist. This compound is central nervous system (CNS) penetrant, and an oral dose of 10 mg/kg NPY5RA-972 to rats produced concentrations in cerebrospinal fluid that greatly exceeded the in vitro IC(50) (inhibitory concentration 50%). Indeed, at doses to rats as low as 1 mg/kg, NPY5RA-972 inhibited feeding induced by intracerebroventricular (ICV) administration of a selective NPY Y5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). However, in the dose range 1-10 mg/kg, NPY5RA-972 had no significant effect on food intake in Wistar rats induced to feed by either ICV NPY or 24 h fasting or in free-feeding Wistar or obese Zucker rats. Chronic administration of NPY5RA-972 (10 mg/kg twice daily) had no effect on food intake or body weight in either free-feeding Wistar rats or dietary obese rats. These data indicate that NPY5RA-972 is a potent, selective, orally active, and CNS-penetrant antagonist of the NPY Y5 receptor that prevents feeding driven by activation of this receptor. The data obtained with this antagonist indicate that the NPY Y5 receptor is not a major regulator of feeding in the rat.     

Long-term effects of nutrient intervention on markers of bone remodeling and calciotropic hormones in late-postmenopausal women

BACKGROUND: Adequate intakes of calcium and vitamin D reduce bone loss and fracture risk in the elderly. Other nutrients also affect bone health, and adequate intakes may influence bone turnover and balance. OBJECTIVE: We compared the long-term effects on bone turnover markers and calciotropic hormones of a multinutrient supplement, a calcium and vitamin D supplement, and dietary instruction aimed at increasing calcium intake through foods. DESIGN: Ninety-nine healthy postmenopausal women participated in a 3-y, randomized trial, receiving either 1) supplemental calcium (1450 mg/d) and vitamin D [10 microg (400 IU)/d], 2) calcium, vitamin D, and other nutrients (multinutrient supplement), or 3) dietary instruction (dietary control group). Data are from 83 subjects who completed the trial. RESULTS: Increases over baseline in calcium intakes and serum 25-hydroxyvitamin D concentrations were sustained over 3 y in all treatment groups. Circulating parathyroid hormone concentrations were reduced at year 1 in all treatment groups but trended toward baseline thereafter. Bone turnover markers followed a similar pattern, and none of the changes in biochemical concentrations differed significantly between groups. CONCLUSIONS: All 3 interventions offer long-term feasibility for increasing calcium intake and serum 25-hydroxyvitamin D concentrations. The dietary addition of micronutrients implicated in skeletal physiology confers no obvious bone-sparing effect in healthy postmenopausal women beyond that of calcium and vitamin D alone. The attenuation over time in suppression of parathyroid hormone and bone turnover might help explain why nutrient intervention tends to have less of a bone-sparing effect than do skeletally active medications such as estrogen or bisphosphonates.     

Regional N-acetylaspartate reduction in the hippocampus detected with fast proton magnetic resonance spectroscopic imaging in patients with Alzheimer disease

OBJECTIVE: To detect regional metabolic changes that resemble the expected spatial pattern of neuronal loss in patients with Alzheimer disease (AD). METHODS: Thirty-four patients with AD and 22 healthy control subjects were included in the study. Single-slice fast proton spectroscopic imaging was performed in parallel angulation to the temporal lobes. Proton spectra were selected from the hippocampus, the lateral temporal lobe, and the occipital lobe of both hemispheres to determine metabolite concentration of N-acetylaspartate (NAA), total creatine (tCr), including phosphocreatine and creatine, and choline-containing compounds (Cho). The metabolic ratios of NAA/tCr and Cho/tCr were calculated and compared between patients with AD and healthy volunteers. RESULTS: The NAA/tCr ratios were significantly reduced in the left (F(1,1) = 4.34, P =.04) and right hippocampus (F(1,1) = 9.96, P =.003) in patients with AD. The Cho/tCr ratios remained unchanged in both hippocampi. There was no significant change of either NAA/tCr or Cho/tCr in the lateral temporal and occipital lobes of patients with AD. CONCLUSION: This study provides evidence that fast proton spectroscopic imaging may detect the regional pattern of disturbed neuronal integrity in patients with AD with high spatial resolution in a short acquisition time.     

Combined time-resolved and high-spatial-resolution 3D MRA using an extended adaptive acquisition

PURPOSE: To combine the benefits of time-resolved dynamic imaging and single elliptical centric acquisitions in a reasonable scan time. MATERIALS AND METHODS: A time series of images with moderate spatial resolution was acquired using the 3D Time-Resolved Imaging of Contrast KineticS (3D TRICKS) technique with elliptical centric encoding during contrast arrival. Following venous opacification, a complete large centrically encoded k-space volume was acquired. The high-spatial-frequency portions of this volume were combined with a 3D TRICKS time frame to form a high-resolution image. An additional single image is formed by suppressing background and signal averaging all acquired data, including post-venous low-spatial-frequency data. For this image, 2D temporal correlation analysis is used to suppress low-spatial-frequency vein contributions. Arrival time and spatial correlations are used to suppress background. RESULTS: The 3D TRICKS time frame may be selected to ensure a combined high-resolution image that has optimal central k-space sampling for any vascular region. The single image formed by signal averaging all acquired data has increased contrast-to-noise (CNR) and signal-to-noise (SNR) ratios. CONCLUSION: The advantages of time-resolved and high-spatial-resolution imaging were combined using an extended dual-phase acquisition. Some SNR and CNR gain was achieved by signal averaging. This process is facilitated by background and vein suppression.     

Short echo time MR spectroscopic imaging of the lung parenchyma

PURPOSE: To perform short echo time MR spectroscopic imaging of the lung parenchyma on normal volunteers.MATERIALS AND METHODS: A short echo time projection-reconstruction spectroscopic imaging sequence was implemented on a commercial 1.5T whole body MRI scanner. Images and spectra of the lung parenchyma were obtained from five normal volunteers. Breath-held spectroscopic imaging was also performed.RESULTS: Spectroscopic imaging of short-T2* species allows visualization of different anatomic structures based upon their frequency shifts. A characteristic peak from the parenchyma was seen at three ppm from water frequency.CONCLUSION: Short echo time MR spectroscopic imaging of the lung parenchyma was demonstrated in normal volunteers. This method may improve proton imaging of the lungs and add specificity to the diagnosis of pulmonary disease.     

反应停治疗难治性多发性骨髓瘤25例

1临床资料我院2001-02/2004-01接受2个疗程卡氮芥 环磷酰胺 马法兰 泼尼松 长春新碱或2个疗程长春新碱 阿霉素 地塞米松方案化疗无效或复发的难治性多发性骨髓瘤患者25(男16,女9)例,年龄42～80(中位年龄57.2)岁.单用反应停口服治疗,起始剂量200 mg/d,如无不良反应,每周增加100 mg,根据患者耐受情况,最高剂量为600 mg/d,3 mo为1疗程.服药期间禁止使用糖皮质激素类药物及细胞毒药物.