Bromocriptine for Cocaine Dependence

On the basis of the dopamine depletion theory, bromocriptine has been tested to treat cocaine withdrawal and dependence. The authors conducted a 6-week study with 1 week of pretreatment observation and 5 weeks of a randomized, double-blind, placebo-controlled clinical trial of bromocriptine for DSM-III-R-defined cocaine dependence in methadone-maintained male patients. The bromocriptine group (n = 24) did not differ from the placebo group (n = 26) in self-reported cocaine use, proportion of positive urine toxicology samples, craving for cocaine, resistance to cocaine use, or mood symptoms between the pretreatment baseline and the last week of the clinical trial. Both groups showed significant reduction in self-reported frequency of cocaine use, resistance to craving, and mood symptoms during participation in the protocol. The results of this study are consistent with recent clinical and laboratory findings in primary cocaine users. Despite initially promising pilot studies, recent evidence does not support the efficacy of bromocriptine to reduce cocaine use or craving.     

Regional myocardial function in idiopathic hypertrophic subaortic stenosis. An echocardiographic study.

To assess regional contractility in idiopathic hypertrophic subaortic stenosis (IHSS), a primary myopathic disorder with documented hyperdynamic ventricular contractions, systolic wall thickening and velocity of contraction of the septum and left ventricular posterior wall were measured in echocardiograms from 16 patients with IHSS and 16 normal subjects. The average thickening of the normal septum and posterior wall was 75.9+/-8.8% and 84.8+/-6.3%, respectively. The posterior wall in IHSS thickened by 75.1+/-6.8%. None of these values differed significantly. However, the increase in thickness of the IHSS septum averaged 22.5+/-2.4%, significantly less than that of either the IHSS posterior wall or the normal septum. Velocity measurements confirmed the impression of diminished septal function. The mean velocity of normal septal contraction averaged 37.0+/-2.3 mm/sec, normal posterior wall 42.3+/-2.0 mm/sec and IHSS posterior wall 55.7+/-3.5 mm/sec, whereas the septum in IHSS contracted at the rate of 26.0+/-2.5 mm/sec. Thus, the IHSS septum contracted significantly more slowly than the normal septum or IHSS posterior wall. However, the posterior wall velocity in IHSS was significantly more rapid than that measured in normal ventricles--perhaps to compensate for the septum. Normalization of all velocities for left ventricular end-diastolic internal diameter did not alter the sifnificance of the results. Consideration of IHSS as an asymmetric myopathy based on prior observations of predominantly septal hypertrophy and distorted septal cellular architecture is now supported by the above evidence of functional left ventricular asymmetry. Although the total left ventricular function in IHSS may be hyperdynamic, regional function is not uniform. The septum appears to be hypodynamic, while the contractile capacity of the posterior wall is increased.     

Evidence for the involvement of endogenous opioids in the regulation of gonadotropin secretion in male goldfish, Carassius auratus

The in vivo effects of the opioid receptor antagonist naloxone (NAL) alone, and in combination with des-Gly10[D-Ala6]LHRH ethylamide (LHRH-A) and the dopamine receptor antagonist domperidone (DOM) on serum gonadotropic hormone (GtH) levels in male goldfish, Carassius auratus, were investigated. NAL caused a significant decrease in serum GtH 1 hr following treatment, with a return to control levels by 2 hr. NAL treatment attenuated the stimulation of GtH levels in response to DOM; NAL treatment 2 hr prior to or 2 hr following DOM resulted in a significantly reduced response to DOM. During late recrudescence, NAL pretreatment significantly blocked the stimulatory effects of LHRH-A on serum GtH. During early recrudescence, when LHRH-A alone did not significantly elevate GtH levels, NAL treatment simultaneously with or 1 hr following LHRH-A significantly elevated serum GtH. In DOM-pretreated fish, combined LHRH-A and NAL treatment resulted in a nine-fold increase in serum GtH compared to DOM alone. These data indicate the ability of NAL to both suppress and increase GtH levels in male goldfish. Interactions between NAL, DOM, and LHRH-A suggest that opioids modulate both dopamine and GnRH secretion, and possibly the pituitary sensitivity to GnRH and dopamine, thus affecting GtH levels.     

In vitro and in vivo studies of a VEGF121/rGelonin chimeric fusion toxin targeting the neovasculature of solid tumors

Vascular endothelial growth factor (VEGF) plays a key role in the growth and metastasis of solid tumors. We generated a fusion protein containing VEGF(121) linked by a flexible G(4)S tether to the toxin gelonin (rGel) and expressed this as a soluble protein in bacteria. Purified VEGF(121)/rGel migrated as an 84-kDa homodimer under nonreducing conditions. VEGF(121)/rGel bound to purified, immobilized Flk-1, and the binding was competed by VEGF(121). Both VEGF(121)/rGel and VEGF(121) stimulated cellular kinase insert domain receptor (KDR) phosphorylation. The VEGF(121)/rGel fusion construct was highly cytotoxic to endothelial cells overexpressing the KDR/Flk-1 receptor. The IC(50) of the construct on dividing endothelial cells expressing 10(5) or more KDR/Flk-1 receptors per cell was 0.5-1 nM, as compared with 300 nM for rGel itself. Dividing endothelial cells overexpressing KDR were approximately 60-fold more sensitive to VEGF(121)/rGel than were nondividing cells. Endothelial cells overexpressing FLT-1 were not sensitive to the fusion protein. Human melanoma (A-375) or human prostate (PC-3) xenografts treated with the fusion construct demonstrated a reduction in tumor volume to 16% of untreated controls. The fusion construct localized selectively to PC-3 tumor vessels and caused thrombotic damage to tumor vessels with extravasation of red blood cells into the tumor bed. These studies demonstrate the successful use of VEGF(121)/rGel fusion construct for the targeted destruction of tumor vasculature in vivo.     

Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma,and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity

Three histological variants are known within the family of embryonal rosette-forming neuroepithelial brain tumors. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). In this study, we performed a comprehensive clinical, pathological, and molecular analysis of 97 cases of these rare brain neoplasms, including genome-wide DNA methylation and copy number profiling of 41 tumors. We identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. As such, future WHO classification schemes should consider lumping these variants into a single diagnostic category, such as embryonal tumor with multilayered rosettes (ETMR). We recommend combined LIN28A immunohistochemistry and FISH analysis of the 19q13.42 locus for molecular diagnosis of this tumor category. Recognition of this distinct pediatric brain tumor entity based on the fact that the three histological variants are molecularly and clinically uniform will help to distinguish ETMR from other embryonal CNS tumors and to better understand the biology of these highly aggressive and therapy-resistant pediatric CNS malignancies, possibly leading to alternate treatment strategies.     

Is there a relationship between executive functions and academic success in children with neurofibromatosis type 1?

The present study aimed to compare the executive function (EF) of children with neurofibromatosis type 1 (NF1) to those of typically developing children and to investigate whether those abilities could predict the child's academic success in terms of academic skills and enablers. Twenty-nine children with NF1 and 27 age-and-gender-matched controls (aged 8–16 years) were examined with two tests to measure EF in an ecologically valid manner: the Behavioural Assessment of the Dysexecutive Syndrome in Children (BADS-C) and the parent questionnaire for the Behavior Rating Inventory of Executive Function (BRIEF). In order to evaluate academic success we used the Academic Competence Evaluation Scales (ACES). The performance of the NF1 group was significantly lower on the Water and Key search subtest of the BADS-C and on four scales of the BRIEF: initiate; working memory; plan/organise and organisation of materials. Significant correlations and predictive models via regression analysis were generated for: BADS-C, BRIEF and ACES scores. Based on these findings, children with NF1 have executive dysfunction that partially accounts for their difficulties in academic achievements.