Duration of Antiresorptive Effects of Low‐Dose Zoledronate in Osteopenic Postmenopausal Women: A Randomized,Placebo‐Controlled Trial

Annual intravenous administration of 5 mg zoledronate decreases fracture risk, but the optimal dosing regimen for zoledronate has not been determined. We set out to evaluate the antiresorptive effects of a single administration of lower doses of zoledronate. A total of 180 postmenopausal women with osteopenia enrolled in a double‐blind, randomized, placebo‐controlled trial over 2 years at an academic research center. Participants were randomized to a single baseline administration of intravenous zoledronate in doses of 1 mg, 2.5 mg, or 5 mg, or placebo. The primary endpoint was change in bone mineral density(BMD) at the lumbar spine. Secondary endpoints were change in BMD at the proximal femur and total body, and changes in biochemical markers of bone turnover. After 2 years, the change in spine BMD was greater in each of the zoledronate groups than in the placebo group; values are mean (95% confidence interval [CI]) difference versus placebo: zoledronate 1 mg 4.4% [2.7% to 6.1%]; 2.5 mg 5.5% [3.9% to 7.2%]; 5 mg 5.3% [3.8% to 6.7%], p < 0.001 for each dose). Change in BMD at the total hip was greater in each of the zoledronate groups than the placebo group (mean [95% CI] difference versus placebo: zoledronate 1 mg 2.6% [1.5% to 3.7%]; 2.5 mg 4.4% [3.5% to 5.3%]; 5 mg 4.7% [3.7% to 5.7%], p < 0.001 for each dose). Each of the bone turnover markers, β‐C‐terminal telopeptide of type I collagen (β‐CTX) and procollagen type‐I N‐terminal propeptide (P1NP), was lower in each of the 2.5‐mg and 5‐mg zoledronate groups than the placebo group throughout the trial (p < 0.001 versus placebo for each marker for each dose at each time point). For each endpoint, changes were similar in the 2.5‐mg and 5‐mg zoledronate groups, whereas those in the 1‐mg group were smaller than those in the other zoledronate groups. These data demonstrate that single administrations of zoledronate 1 mg or 2.5 mg produce antiresorptive effects that persist for at least 2 years. Trials assessing the antifracture efficacy of intermittent low doses of zoledronate, in particular the 2.5‐mg dose, are justified. © 2014 American Society for Bone and Mineral Research.     

Meriolins, a new class of cell death inducing kinase inhibitors with enhanced selectivity for cyclin-dependent kinases

Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1alpha, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms.     

Facilitation of learning by social-emotional feedback in humans is beta-noradrenergic-dependent

Adaptive behavior in dynamic environments critically depends on the ability to learn rapidly and flexibly from the outcomes of prior choices. In social environments, facial expressions of emotion often serve as performance feedback and thereby guide declarative learning. Abundant evidence implicates beta-noradrenergic signaling in the modulatory influence of emotion on declarative learning. It is currently unclear whether a similar mechanism also mediates a guidance of declarative learning by social-emotional feedback administered in the form of facial expressions. We therefore conducted a double-blind randomized placebo-controlled trial to test the effects of a 40-mg single oral dose of the nonspecific beta-noradrenergic antagonist propranolol in a behavioral task that required gradual declarative learning of item-category associations from either social-emotional (happy vs. angry faces) or nonsocial (green vs. red color signals) trial-by-trial feedback. As predicted on the basis of our previous experiments, learning from social-emotional feedback was more effective than learning from nonsocial feedback in placebo-treated subjects. This advantage of social-emotional over nonsocial feedback was abolished by propranolol treatment. Propranolol had no effect on learning during the nonsocial feedback condition. Our findings suggest that a facilitation of declarative learning by social-emotional feedback critically involves signaling via beta-noradrenergic receptors.     

Role of transesophageal echocardiography in percutaneous aortic valve replacement with the CoreValve Revalving system

Percutaneous aortic valve replacement (PAVR) is an emerging therapy for nonsurgical patients with severe aortic stenosis (AS). We examined the role of transesophageal echocardiography (TEE) in PAVR. TEE was used initially to assess the native valve and aortic root, and served as a guide during PAVR. Following prosthetic valve deployment, TEE was used to assess valve function. Eleven patients aged 82 +/- 10 years with NYHA III-IV underwent PAVR. Periprocedural TEE gave immediate information on prosthetic position and function, LV function, mitral regurgitation, pericardium, and thoracic aorta anatomy. There was excellent visual agreement between fluoroscopic and TEE images of prosthetic positioning and deployment. TEE facilitated the detection and management of procedure-related complications. Compared with pre-PAVR, AV area (0.56 +/- 0.19 cm(2) vs. 1.3 +/- 0.4 cm(2); P < 0.001) and LVEF (49 +/- 17% vs. 56 +/- 11%; P < 0.001) increased. TEE provides key anatomical and functional information, and serves as a diagnostic guide for complications, which may arise during PAVR.     

Inhaled milrinone: a new alternative in cardiac surgery?

The administration of milrinone through inhalation has been studied in only a few animal and human studies. Compared to the intravenous administration, inhaled milrinone has been shown to reduce pulmonary artery pressure without systemic hypotension. Therefore, this approach could represent an alternative to nitric oxide. This current state of knowledge of intravenous and inhaled milrinone is presented and summarized.     

Overnight deprivation from smoking disrupts amygdala responses to fear

Cigarette smoking, a major, yet avoidable, cause of disability and premature death, is the most prevalent form of nicotine addiction. An emerging theme in the neurobiology of nicotine addiction is the integrity of the amygdala. Using functional MRI, amygdala responses during a face perception task were compared between 28 chronic smokers [14 females, 14 males; age, 26.3 (2.8) years; age at onset of smoking, 15.8 (2.6) years; years smoked, 9.1 (2.1); cigarettes per day, 17.1 (3.7); Fagerström test for nicotine dependence score, 4.1 (1.9); exhaled carbon‐monoxide level, 17.8 (9.5) ppm] and 28 age‐ and education‐matched nonsmokers [14 females, 14 males; age, 26.9 (2.4) years]. Subjects underwent imaging on two separate occasions 1 week apart: smoking satiety versus overnight smoking deprivation, in a randomized counterbalanced order. Our results show no difference in amygdala responses to faces between nonsmokers and satiated smokers. However, overnight deprivation from smoking was associated with a significantly lowered amygdala response to fear, an effect that was probabilistically mapped to the basolateral amygdala. We suggest that aberrant amygdala reactivity in overnight‐deprived smokers may reflect a pre‐existing vulnerability to smoking and/or increase the risk of smoking relapse after a cessation attempt. Hum Brain Mapp, 2011. © 2011 Wiley‐Liss, Inc.