Efficacy and safety of gadodiamide (Gd-DTPA-BMA) in renal 3D-magnetic resonance angiography (MRA): a phase II study

PURPOSE: To determine the most efficacious dose of gadodiamide for three-dimensional (3D) contrast-enhanced (CE) magnetic resonance angiography (MRA) of the renal arteries on a patient level based on the sensitivity in detecting the main hemodynamically relevant (> or =50% or occlusion) renal artery stenosis (RAS) using intra-arterial digital subtraction angiography (IA DSA) as the gold standard. MATERIALS AND METHODS: This prospective, randomized, double-blind, parallel-group, multicenter study included 273 patients referred to IA DSA for suspected RAS. Patients underwent 3D CE MRA after injection of 0.01, 0.05, 0.1, or 0.2mmol/kg of body weight gadodiamide (0.5mmol/ml). The images were assessed for location and degree of RAS by independent blinded readers (MRA: three readers, IA DSA: one reader). Hypothesis testing for a significant trend in sensitivity across dose groups was based on the one-sided Cochran-Armitage style trend test for each independent MRA reader. RESULTS: The lowest dose group (0.01mmol/kg) proved non-efficacious in detecting hemodynamically relevant (i.e., > or =50% or occlusion) RAS. A statistically significant dose trend (p<0.001) was shown for each of the three independent readers. Depending on reader, the sensitivity obtained with 0.05, 0.1, and 0.2mmol/kg was 63.9-86.1%, 75.8-91.4% and 80.6-90.6%, the specificity was 66.7-73.9%, 59.3-75.0%, and 59.3-75.0% and accuracy was 67.8-78.9%, 75.4-77.4%, and 76.3-81.0%, for the three dose groups, respectively. There were eight non-severe adverse events (AEs). Three serious AEs occurring in one patient were judged not related to gadodiamide by the on-site investigator. CONCLUSION: A significant dose trend between the four doses examined was observed. The lowest dose (0.01mmol/kg) differed significantly from those of the other three doses. Based on the analysis of the primary and secondary endpoints, 0.1mmol/kg gadodiamide appears to be the most suitable dose in diagnosing hemodynamically relevant RAS. The present study also demonstrated gadodiamide to be safe and well tolerated.     

Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and peritumoral angiogenesis

Infiltration of cancer cells into normal tissue is a hallmark of malignant gliomas and compromises treatment options. A lack of appropriate models limits the study of this invasion in vivo, which makes it difficult to fully understand its anatomy and the role of dynamic interactions with structures of the normal brain. We developed a novel methodology by utilizing multiphoton laser scanning microscopy (MPLSM) to image the movement of glioma cells deep within the normal brain of live mice in real time. This allowed us to track the invasion of individual RFP‐expressing GL261 cells in relation to perfused vasculature or GFP‐labeled endothelial cells repetitively over days, up to a depth of 0.5 mm. Glioma cells moved faster and more efficiently when the abluminal site of a blood vessel was utilized for invasion. Cells that invaded perivascularly were frequently found next to (a) multiple capillary structures where microvessels run parallel to each other, (b) capillary loops or glomeruloid‐like bodies, and (c) dilated capillaries. Dynamic MPLSM for more than 48 h revealed that single invasive glioma cells induced intussusceptive microvascular growth and capillary loop formation, specifically at the microvascular site with which they had contact. As the main tumor grew by cooption of existing brain vessels, these peritumoral vascular changes may create a beneficial environment for glioma growth. In conclusion, our study revealed new mechanisms of peritumoral angiogenesis and invasion in gliomas, providing an explanation for their interdependence. © 2009 Wiley‐Liss, Inc.     

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+ and ALK? anaplastic large-cell lymphoma

Aberrant anaplastic lymphoma kinase (ALK) expression is a defining feature of many human cancers and was identified first in anaplastic large-cell lymphoma (ALCL), an aggressive non-Hodgkin T-cell lymphoma. Since that time, many studies have set out to identify the mechanisms used by aberrant ALK toward tumorigenesis. We have identified a distinct profile of micro-RNAs (miRNAs) that characterize ALCL; furthermore, this profile distinguishes ALK⁺ from ALK⁻ subtypes, and thus points toward potential mechanisms of tumorigenesis induced by aberrant ALK. Using a nucleophosmin-ALK transgenic mouse model as well as human primary ALCL tumor tissues and human ALCL-derived cell lines, we reveal a set of overlapping deregulated miRNAs that might be implicated in the development and progression of ALCL. Importantly, ALK⁺ and ALK⁻ ALCL could be distinguished by a distinct profile of “oncomirs”: Five members of the miR-17–92 cluster were expressed more highly in ALK⁺ ALCL, whereas miR-155 was expressed more than 10-fold higher in ALK⁻ ALCL. Moreover, miR-101 was down-regulated in all ALCL model systems, but its forced expression attenuated cell proliferation only in ALK⁺ and not in ALK⁻ cell lines, perhaps suggesting different modes of ALK-dependent regulation of its target proteins. Furthermore, inhibition of mTOR, which is targeted by miR-101, led to reduced tumor growth in engrafted ALCL mouse models. In addition to future therapeutical and diagnostic applications, it will be of interest to study the physiological implications and prognostic value of the identified miRNA profiles.     

Insomnia in depression: differences in objective and subjective sleep and awakening quality to normal controls and acute effects of trazodone

Utilizing polysomnography (PSG) and psychometry, objective and subjective sleep and awakening quality was investigated in 11 drug-free patients (five females, six males) aged 35-75 years (mean age 54.1 +/- 11.4) suffering from nonorganic insomnia (F 51.0) related to a depressive episode (F 32) or recurrent depressive disorder (F 33). as compared with 11 age- and sex-matched normal controls (five females, six males) aged 36-75 years (mean age 53.0 +/- 13.5). PSG demonstrated decreased sleep efficiency, total sleep time (TST), total sleep period (TSP) and sleep stage S2, as well as increased wakefulness during TSP, early morning awakening, sleep latency to S1, S2, S3 and sleep stage S1 in depressed patients. Subjective sleep quality and the total score of the Self-Assessment of Sleep and Awakening Quality Scale (SSA) were deteriorated as were morning and evening well being, drive, mood and fine motor activity right. Evening and morning blood pressure, the O2 desaturation index and periodic leg movement (PLM) index were increased. In a subsequent acute, placebo-controlled cross-over design study, the acute effects of 100 mg of trazodone, a serotonin reuptake inhibitor with a sedative action due to 5-HT2 and alpha1 receptor blockade, were investigated in the patients. As compared with placebo, trazodone induced an increase in sleep efficiency (primary target variable), TST, TSP and SWS (S3 + S4), as well as a decrease in wakefulness during the TSP, early morning awakening and S2. There was no change in rapid eye movement (REM) sleep with the exception of an increase in the REM duration in minutes. Trazodone also caused an improvement in subjective sleep quality, affectivity, numerical memory and somatic complaints. All respiratory variables remained within normal limits. Critical flicker frequency and moming diastolic blood pressure were decreased. The present study demonstrated that depression induced significant changes in objective and subjective sleep and awakening quality, which were counteracted by 100 mg of trazodone, thus suggesting a key-lock principle in the treatment of depression.     

Home or Nursing Home: Does Place of Residence Affect Longevity in Patients With Alzheimer's Disease? The Experience of CERAD Patients

ABSTRACT There is concern that life is curtailed when patients with Alzheimer's disease (AD) are institutionalized. To determine whether placement in a nursing home reduces their remaining years of life, we examined the experience of White patients with AD ( n =890) enrolled in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Proportional hazards survival analysis using the landmark approach (with the landmark set to 12 months after CERAD entry and reevaluated at succeeding 6-month time intervals through 5 years) indicated that longevity at home and in the nursing home was comparable. Thus, in these patients enrolled at tertiary care medical centers, living at home or in a nursing home did not affect time to death. These data suggest that when home care is no longer feasible, families and nurses counseling them should not feel that they are curtailing life by placing an AD patient in a nursing home.     

Evaluation of subclinical cerebral injury and neuropsychologic function in patients undergoing carotid endarterectomy

We examined subclinical alterations of cerebral function during carotid endarterectomy (CEA) and predictability of minor cerebral damage by perioperative levels of biochemical markers of brain damage (S100B and neuron-specific enolase [NSE]). Twenty consecutive patients with > or =70% asymptomatic carotid stenosis undergoing elective CEA were enrolled. Pre- and postoperative testing included magnetic resonance imaging (MRI) of the head, a standardized neurological exam, a battery of neuropsychological tests, and measurement of serum levels of S100B and NSE. There were no major ischemic strokes. In one patient, a mild weakness of the contralateral lower extremity was discovered on neurological examination; in another individual, postoperative MRI revealed two new small subcortical lesions without clinical correlate. While S100B increased significantly early after opening of the carotid clamp (p = 0.015), the NSE increase did not reach statistical significance. As a group, participants obtained a significantly higher mean overall neuropsychological score at follow-up testing (p < 0.05). In one patient, a significant decline of cognitive function was observed. This was the only individual to obtain a consistently high S100B and NSE increase. Neuropsychological testing combined with measurements of S100B and NSE may improve sensitivity when assessing subtle cerebral damage following CEA.     

Personal goals and factors related to QoL in Dutch homeless people: what is the role of goal‐related self‐efficacy?

Very little is known about the personal goals of homeless people and how these relate to their quality of life (QoL). By using survey data on 407 homeless adults upon entry to the social relief system in 2011, we examined the personal goals of homeless adults and the association between their perceived goal‐related self‐efficacy and their QoL. A hierarchical regression analysis was used to analyse the association between QoL and goal‐related self‐efficacy, relative to factors contributing to QoL, such as demographic characteristics, socioeconomic resources, health and service use. Results indicate that the majority of homeless adults had at least one personal goal for the coming 6 months and that most goals concerned housing and daily life (94.3%) and finances (83.6%). The QoL of homeless adults appeared to be lower in comparison with general population samples. General goal‐related self‐efficacy was positively related to QoL (β = 0.09, P = 0.042), independent of socioeconomic resources (i.e. income and housing), health and service use. The strongest predictors of QoL were psychological distress (β = ?0.45, P < 0.001), income (β = 0.14, P = 0.002) and being institutionalised (β = 0.12, P = 0.004). In conclusion, the majority of homeless adults entering the social relief system have personal goals regarding socioeconomic resources and their goal‐related self‐efficacy is positively related to QoL. It is therefore important to take the personal goals of homeless people as the starting point of integrated service programmes and to promote their goal‐related self‐efficacy by strength‐based interventions.