Multiple sclerosis: serial study of gadolinium-enhanced MR imaging

Thirteen patients with definite multiple sclerosis (MS), studied 16-24 months previously with magnetic resonance (MR) imaging with and without enhancement by intravenously administered gadolinium diethylenetriaminepentaacetic acid (DTPA) dimeglumine, were reexamined with a similar protocol. Assessment of enhancement and clinical activity in both studies revealed that enhancement was observed in 13 of 14 cases in which clinical activity had changed within 4 weeks of the study and thus appeared more sensitive than clinical examination in determining active disease. The 3-minute postinjection, short repetition time image (TR) was the most efficient for depicting enhancement. Enhancing lesions (active plaques) arose from previously hyper- or isointense regions on long TR images. Previously active lesions reverted to areas of iso- or hyperintensity on long TR images. Serial comparison of long TR images in this population reveals a decrease in high-intensity lesions on long TR images in some cases and an increase in others. The findings of high-intensity regions on long TR images and previously enhancing lesions both becoming isointense suggests that transient inflammatory changes with concomitant edema without demyelination and/or with significant remyelination may occur in some MS lesions. MS lesions are dynamic; both active and inactive lesions may show dramatic change on longitudinal MR imaging studies.     

Adamantyl cannabinoids: a novel class of cannabinergic ligands

Structure-activity relationship studies have established that the aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids. We have now synthesized a series of analogues in which a variety of adamantyl substituents were introduced at the C3 position of Delta(8)-THC. Our lead compound, (-)-3-(1-adamantyl)-Delta(8)-tetrahydrocannabinol (1a, AM411), was found to have robust affinity and selectivity for the CB1 receptor as well as high in vivo potency. The X-ray crystal structure of 1a was determined. Exploration of the side chain conformational space using molecular modeling approaches has allowed us to develop cannabinoid side chain pharmacophore models for the CB1 and CB2 receptors. Our results suggest that although a bulky group at the C3 position of classical cannabinoids could be tolerated by both CB1 and CB2 binding sites, the relative orientation of that group with respect to the tricyclic component can lead to receptor subtype selectivity.     

Shear Bond Strengths of One-Bottle Adhesives to Oil-Contaminated Enamel

Purpose: To evaluate resin bond strength to enamel contaminated with handpiece oil. Materials and Methods: Bovine teeth were randomly assigned to six groups of 20 teeth each for treatment with one of six different bonding systems (five one‐bottle and one multibottle). For each system, 10 enamel specimens were contaminated with handpiece oil before acid‐etching and 10 were contaminated after acid‐etching. The enamel was etched for 15 seconds using 35% phosphoric acid. Following adhesive application, composite resin was bonded using a gelatin capsule technique. Shear bond strengths from the two contaminated groups were compared to bond strengths to uncontaminated enamel obtained from a previous study that was performed by the same group of investigators, using the same facility, materials, and methods. Results: Two‐way analysis of variance (ANOVA) showed that the factor “surface contamination” did not have a significant effect on bond strength (p > .542). The type of adhesive and the interaction of adhesive and surface contamination were significant (p <.0001 and p <.003, respectively). When oil was applied before etching, mean bond strengths ranged from 18.0 ± 4.8 MPa for OptiBond SOLO (Kerr Corp., Orange, California) to 25.3 ± 5.6 MPa for Tenure Quik with Fluoride (Den‐Mat Corp., Santa Maria, California). With oil applied after etching, bond strengths ranged from 18.4 ± 8.0 MPa for Tenure Quik with Fluoride to 27.4 ± 5.4 MPa for Single Bond (3M Dental Products, St. Paul, Minnesota). For the same adhesive, comparing uncontaminated and “oil‐before‐etch” contaminated groups, the only statistically significant difference in bond strengths was for OptiBond SOLO: 21.8 ± 4.0 MPa (uncontaminated) versus 18.0 ± 4.8 MPa (oil before etch). Comparing uncontaminated and “oil‐after‐etch” groups, the only statistically significant difference was for Tenure: 24.5 ± 5.7 MPa (uncontaminated) and 18.4 ± 8.0 MPa (oil after etch). CLINICAL SIGNIFICANCE Surface contamination with handpiece lubricant oil does not impair appreciably the efficacy of the adhesives used in this study when bonding composite resin to enamel.     

A genetic risk score predicts coronary artery disease in familial hypercholesterolaemia: enhancing the precision of risk assessment

Familial hypercholesterolaemia (FH) is associated with increased risk of coronary artery disease (CAD); however, risk prediction and stratification remain a challenge. Genetic risk scores (GRS) may have utility in identifying FH patients at high CAD risk. The study included 811 patients attending the lipid disorders clinic at Royal Perth Hospital with mutation-positive (n = 251) and mutation-negative (n = 560) FH. Patients were genotyped for a GRS previously associated with CAD. Associations between the GRS, clinical characteristics, and CAD were assessed using regression analyses. The average age of patients was 49.6 years, and 44.1% were male. The GRS was associated with increased odds of a CAD event in mutation-positive [odds ratio (OR) = 3.3; 95% confidence interval (CI) = 1.3-8.2; P = .009] and mutation-negative FH patients (OR = 1.8; 95% CI = 1.0-3.3; P = .039) after adjusting for established predictors of CAD risk. The GRS was associated with greater subclinical atherosclerosis as assessed by coronary artery calcium score (P = .039). A high GRS was associated with CAD defined clinically and angiographically in FH patients. High GRS patients may benefit from more intensive management including lifestyle modification and aggressive lipid-lowering therapy. Further assessment of the utility of the GRS requires investigation in prospective cohorts, including its role in influencing the management of FH patients in the clinic.     

力竭运动大鼠心室肌蛋白质组表达特征

目的:采用蛋白质组学技术,建立安静和递增运动负荷训练后力竭大鼠心室肌蛋白质组的差异性表达谱,初步筛选出心室肌对力竭运动产生反应的目标蛋白质。方法:实验于2007-03在湖南师范大学生命科学学院蛋白质化学与蛋白质组学国家教育部重点实验室和省级运动人体科学实验室完成。①实验分组:10只SD雄性大鼠随机分为对照组和运动组,每组5只。②实验方法:运动组经过7周的大强度递增运动负荷训练后(最后一次力竭),对两组心室肌组织的全蛋白进行双向凝胶电泳分离。结果:经图像分析,在运动组的电泳图谱上共展现蛋白质点(338±17)个,对照组展现蛋白质点(352±17)个。运动后差异表达的蛋白质点共有99个。对其中差异表达的9个蛋白质点进行质谱鉴定,共鉴定出7个蛋白质,Stress-70protein,NADH-ubiquinone oxidoreductase Mr75000subnunit,Long-chain specific acyl-CoA dehydrogenase,Tropomyosin-1alphachain在运动后"缺失",Nitrilase family,member2在运动后表达上调在5倍以上,一个相对分子质量为21000的未知蛋白在运动后表达下调在5倍以上,另外有两个点经鉴定均为Myosin-6,在运动后表达量相反。这些蛋白质属于收缩蛋白、能量代谢酶、分子伴侣等。结论:递增运动负荷训练后力竭时,大鼠心室肌蛋白质组明显地发生了反应。运动后"缺失"和下调的蛋白质点与心肌收缩的调控和能量代谢的方式转变以及细胞的应激反应有关,其中,成功筛选出6种在运动医学领域尚未涉足的、具有运动应激特点的目标蛋白质。     

Bradycardia and Syncope in Children Not Controlled by Pacing: Beta-Adrenergic Hypersensitivity

Cardiac pacing is frequently employed in the therapy of children with syncope and documented bradycardia. This report describes two children, ages 7 and 9 years, who underwent placement of demand ventricular pacing systems for documented bradycardia and syncope. Cardiac catheterization and intracardiac electrophysiological studies failed to show evidence of structural abnormalities, sinus node or conduction system disease, inducible arrhythmias, or VA conduction in each patient. Both patients had persistent symptoms after pacemaker implantation. Autonomic function testing with continuous heart rate and blood pressure monitoring revealed exaggerated beta-adrenergic responses to simple standing and small doses of isoproterenol. Symptoms were completely eliminated with atenolol. In these two children, cardiac pacing alone was not adequate for relief of symptoms. Autonomic mechanisms of bradycardia and hypotension should be considered prior to implantation of permanent pacing systems in children.     

Characteristics of human large granular lymphocytes and relationship to natural killer and K cells

Recent evidence, has demonstrated an association between a subpopulation of peripheral blood mononuclear cells, morphologically identified as large granular lymphocytes (LGL), and natural killer (NK) activity. We have now evaluated more directly the role of LGL in both NK activity and antibody- dependent cellular cytotoxicity (ADCC), by using highly enriched populations of LGL, obtained by centrifugation of peripheral blood mononuclear cells on Percoll discontinuous density gradients. Both spontaneous and interferon- augmented NK and ADCC activities were exclusively associated with the LGL- enriched, low density fractions. The majority of LGL formed conjugates with NK-susceptible and antibody-coated target cells. Approximately 20 percent of small conventional lymphocytes also formed conjugates with the target cells for NK, but this was not associated with cytotoxic activity. Virtually all LGL were found to have receptors for the Fc portion of IgG (FcγR). The frequency of LGL among blood leukocytes was 2-6 percent. LGL could be enriched to an average purity of 95 percent by combining discontinuous density gradient centrifugation with subsequent adsorptions of the low density fractions on monolayers of immobilized immune complexes. About 50 percent of LGL were found to be FcγR-bearing T cells (T(G)), forming low affinity rosettes with sheep erythrocytes at 4 degrees C. Only 10-20 percent of LGL formed high affinity rosettes with sheep erythrocytes at 29 degrees C. LGL could be enriched to a purity of more than 90 percent by depleting high affinity rosette-forming cells from low density Percoll fractions. LGL were only a subpopulation of T(G) cells, because some lymphocytes with conventional morphology also adhered to the immobilized immune complex monolayers and formed high affinity rosettes with sheep erythrocytes. Separation of these cells from LGL by discontinuous density gradient centrifugation indicated that they are not cytotoxic, suggesting a morphological and functional subdivision of T(G) cells. The verification in this study that virtually all human NK and K cells have a characteristic morphology adds a useful parameter to the monitoring of human lymphocytes, and the ability to purify these cells by simple physical procedures should be invaluable in their further characterization.