A Comprehensive Map of CNS Transduction by Eight Recombinant Adeno-associated Virus Serotypes Upon Cerebrospinal Fluid Administration in Pigs

Cerebrospinal fluid administration of recombinant adeno-associated viral (rAAV) vectors has been demonstrated to be effective in delivering therapeutic genes to the central nervous system (CNS) in different disease animal models. However, a quantitative and qualitative analysis of transduction patterns of the most promising rAAV serotypes for brain targeting in large animal models is missing. Here, we characterize distribution, transduction efficiency, and cellular targeting of rAAV serotypes 1, 2, 5, 7, 9, rh.10, rh.39, and rh.43 delivered into the cisterna magna of wild-type pigs. rAAV9 showed the highest transduction efficiency and the widest distribution capability among the vectors tested. Moreover, rAAV9 robustly transduced both glia and neurons, including the motor neurons of the spinal cord. Relevant cell transduction specificity of the glia was observed after rAAV1 and rAAV7 delivery. rAAV7 also displayed a specific tropism to Purkinje cells. Evaluation of biochemical and hematological markers suggested that all rAAV serotypes tested were well tolerated. This study provides a comprehensive CNS transduction map in a useful preclinical large animal model enabling the selection of potentially clinically transferable rAAV serotypes based on disease specificity. Therefore, our data are instrumental for the clinical evaluation of these rAAV vectors in human neurodegenerative diseases.     

Do trauma teams make a difference? : A single centre registry study

OBJECTIVE: To evaluate the association between trauma team activation according to well-established protocols and patient survival. METHODS: Single centre, registry study of data collected prospectively from trauma patients (who were treated in a trauma resuscitation room, who died or who were admitted to ICU) of a tertiary referral trauma centre Emergency Department (ED) in Hong Kong. A 10-point protocol was used to activate rapid trauma team response to the ED. The main outcome measures were mortality, need for ICU care, or operation within 6h of injury. RESULTS: Between 1 January 2001 and 31 December 2005, 2539 consecutive trauma patients were included in our trauma registry, of which 674 patients (mean age 43 years, S.D. 22; 71% male; 94% blunt trauma) met trauma call criteria. Four hundred and eighty two (72%) correctly triggered a trauma call, and 192 (28%) were not called ('undercall'). Patients were less likely to have a trauma call despite meeting criteria if they were aged over 64 years, had sustained a fall, had a respiratory rate <10 or >29 per minute, a systolic blood pressure between 60 and 89 mm Hg, or a GCS of 9-13. In a sub-group of moderately poor probability of survival (probability of survival, P(s), 0.5-0.75), the odds ratio for mortality in the undercall group compared with the trauma call group was 7.6 (95% CI, 1.1-33.0). CONCLUSIONS: In our institution, undercalls account for 28% of patients who meet trauma call criteria and in patients with moderately poor probability of survival undercall is associated with decreased survival. Although trauma team activation does not guarantee better survival, better compliance with trauma team activation protocols optimises processes of care and may translate into improved survival.     

Retention of CPR skills learned in a traditional AHA Heartsaver course versus 30-min video self-training: a controlled randomized study

BACKGROUND: Bystander CPR improves outcomes after out of hospital cardiac arrest. The length of current 4-h classes in cardiopulmonary resuscitation (CPR) is a barrier to more widespread dissemination of CPR training and older adults in particular are underrepresented in traditional classes. Training with a brief video self-instruction (VSI) program has shown that this type of training can produce short-term skill performance at least as good as that seen with traditional American Heart Association (AHA) Heartsaver training, although it is unclear whether there is comparable skill retention. METHODS AND RESULTS: Two hundred and eight-five adults between the ages of 40 and 70 who had no CPR training within the past 5 years were assigned at random to a no-training control group, Heartsaver (HS) training, or one of three versions of brief VSI (i.e., self-trained-ST subjects). Post-training performance of CPR skills was assessed in a scenario format by human examiners and by sensored manikin at Time 1 (immediately post-training) and again at Time 2 (2 months post-training). Performance by controls was assessed only once. Significant (P<.001) decline was observed in the three measures recorded by examiners; assess responsiveness (from 72% to 60% for HS subjects and from 90% to 77% for ST subjects), call 911 (from 82% to 74% for HS subjects and from 71% to 53% for ST subjects), and overall performance (from 42% to 30% for HS subjects and from 60% to 44% for ST subjects). Significant (P<.001) decline was observed in two of three skills measured by a sensored manikin: ventilation volume (from 40% to 36% for HS subjects and from 61% to 41% for ST subjects, with a significant [P=.028] interaction) and correct hand placement (from 68% to 59% for HS subjects and from 80% to 64% for ST subjects). Heartsaver and self-trained subjects generally showed similar rates of decline. At Time 2, examiners rated trained subjects better than untrained controls in all skills except calling 911, where self-trained subjects did not differ from controls; manikin data revealed that trained subjects' performance was better than that of controls for ventilation volume, but had declined to the level of controls for both hand placement and compression depth. CONCLUSIONS: Adults between 40 and 70 years of age who participated in a CPR VSI program experienced performance decline in their CPR skills after a post-training interval of 2 months. However, this decline was no greater than that seen in subjects who took Heartsaver training. The VSI program produced retention performance at least as good as that seen with traditional training. Additional effort is needed to improve both initial performance and retention of CPR skills. CONDENSED ABSTRACT: Retention of CPR skills was compared 2 months post-training for adults between 40 and 70 years old who had taken either a traditional Heartsaver CPR course or a 22-min video self-directed training course. Although performance declines occurred in the 2-month interval, self-trained subjects generally demonstrated CPR skill retention equivalent to that of Heartsaver-trained subjects, although for both groups skill decline on some measures reached the level of untrained controls.     

Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1)

Large clonal expansions of peripheral CD8+ T cells carrying receptors for single epitopes of CMV and EBV are common in the elderly and may be associated with an immune risk phenotype predicting mortality. Here we show that the frequency of CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1), a marker of cells unable to undergo further clonal expansion, was markedly elevated in CD8+ T cells from old donors. Moreover, tetramer staining revealed that the elevated frequency of CMV-specific CD8+ T cells in the elderly was due to an accumulation of cells bearing this dominant negative receptor. The fraction of CMV-specific T cells able to secrete interferon-gamma after specific antigenic stimulation was significantly lower in the elderly than in the young, although the total number of functional cells was comparable. Therefore, the majority of the clonally expanded virus-specific CD8+ cells in the elderly was dysfunctional. Thus, T cell responses are altered in the aged by an accumulation of replicatively senescent dysfunctional T cells carrying receptors for persistent herpes viruses. The presence of clonal expansions of such virus-specific cells may shrink the available repertoire for other antigens and contribute to the increased incidence of infectious disease in the elderly.     

Multimodal neuroimaging evidence of alterations in cortical structure and function in HIV‐infected older adults

Combination antiretroviral therapy transformed human immunodefiency virus (HIV)‐infection from a terminal illness to a manageable condition, but these patients remain at a significantly elevated risk of developing cognitive impairments and the mechanisms are not understood. Some previous neuroimaging studies have found hyperactivation in frontoparietal networks of HIV‐infected patients, whereas others reported aberrations restricted to sensory cortices. In this study, we utilize high‐resolution structural and neurophysiological imaging to determine whether alterations in brain structure, function, or both contribute to HIV‐related cognitive impairments. HIV‐infected adults and individually matched controls completed 3‐Tesla structural magnetic resonance imaging (sMRI) and a mechanoreception task during magnetoencephalography (MEG). MEG data were examined using advanced beamforming methods, and sMRI data were analyzed using the latest voxel‐based morphometry methods with DARTEL. We found significantly reduced theta responses in the postcentral gyrus and increased alpha activity in the prefrontal cortices of HIV‐infected patients compared with controls. Patients also had reduced gray matter volume in the postcentral gyrus, parahippocampal gyrus, and other regions. Importantly, reduced gray matter volume in the left postcentral gyrus was spatially coincident with abnormal MEG responses in HIV‐infected patients. Finally, left prefrontal and postcentral gyrus activity was correlated with neuropsychological performance and, when used in conjunction, these two MEG findings had a sensitivity and specificity of over 87.5% for HIV‐associated cognitive impairment. This study is the first to demonstrate abnormally increased activity in association cortices with simultaneously decreased activity in sensory areas. These MEG findings had excellent sensitivity and specificity for HIV‐associated cognitive impairment, and may hold promise as a potential disease marker. Hum Brain Mapp 36:897–910, 2015. © 2014 Wiley Periodicals, Inc.     

Systemic ventricular function in patients with transposition of the great arteries after atrial repair: a tissue Doppler and conductance catheter study

OBJECTIVES: The aim of this study was to assess the utility of tissue Doppler echocardiography in the setting of repaired transposition of the great arteries when the right ventricle (RV) functions as the systemic ventricle. BACKGROUND: Myocardial acceleration during isovolumic contraction, "isovolumic myocardial acceleration" (IVA), has been validated as a sensitive non-invasive method of assessing RV contractility. Although traditional indexes may be less valid for the abnormal RV, the relative insensitivity of IVA to an abnormal load makes it a potentially powerful clinical tool for the assessment of RV disease. METHODS: We examined 55 controls and 80 patients (mean age 22 years) with transposition, who had undergone atrial repair at age 8 (0.3 to 72) months. A subgroup of 12 underwent cardiac catheterization. The RV systolic function was derived by analysis of pressure-volume relationships and IVA both at rest and during dobutamine stress. In all 80, myocardial velocities were sampled in the RV free wall. RESULTS: During dobutamine (10 microg/kg/min for 10 min), the increase of IVA mirrored the increase in end-systolic elastance (r = 0.69, p < 0.02). In the group as a whole, IVA was reduced compared with the subpulmonary RV and the systemic left ventricle of controls. There was abnormal wall motion in 44 patients, which was associated with reduced IVA. Diastolic myocardial velocities were also abnormal but unrelated to the presence of wall motion abnormalities. CONCLUSIONS: The IVA can accurately assess changes in RV contractile function in patients with an RV as the systemic ventricle. Global long-axis RV function is reduced in patients with transposition, and this is associated with abnormal regional function.     

Phase I Study of Nintedanib Incorporating Dynamic Contrast‐Enhanced Magnetic Resonance Imaging in Patients With Advanced Solid Tumors

Background.

This open-label phase I dose-escalation study investigated the safety, efficacy, pharmacokinetics (PK), and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) effects of the oral angiokinase inhibitor nintedanib in patients with advanced solid tumors.

Methods.

Nintedanib was administered once daily continuously, starting at 100 mg and later amended to allow evaluation of 250 mg b.i.d. The primary endpoint was maximum tolerated dose (MTD). DCE-MRI studies were performed at baseline and on days 2 and 28.

Results.

Fifty-one patients received nintedanib 100–450 mg once daily (n = 40) or 250 mg b.i.d. (n = 11). Asymptomatic reversible liver enzyme elevations (grade 3) were dose limiting in 2 of 5 patients at 450 mg once daily. At 250 mg b.i.d., 2 of 11 patients experienced dose-limiting toxicity (grade 3 liver enzyme elevation and gastrointestinal symptoms). Common toxicities included fatigue, diarrhea, nausea, vomiting, and abdominal pain (mainly grade ≤2). Among 45 patients, 22 (49%) achieved stable disease; 7 remained on treatment for >6 months. DCE-MRI of target lesions revealed effects in some patients at 200 and ≥400 mg once daily.

Conclusion.

Nintedanib is well tolerated by patients with advanced solid malignancies, with MTD defined as 250 mg b.i.d., and can induce changes in DCE-MRI. Disease stabilization >6 months was observed in 7 of 51 patients.