Citations

BackgroundThere are no effective treatments that slow the progression of neurodegenerative diseases. A major challenge of treatment in neurodegenerative diseases is appropriate delivery of pharmaceuticals into the cerebrospinal fluid (CSF) of affected individuals. Mesenchymal stromal cells (MSCs—either naïve or modified) are a promising therapy in neurodegenerative diseases and may be delivered directly into the CSF where they can reside for months. In this preclinical study, we evaluated the safety of intrathecal autologous MSCs in a rabbit model.Study Design and MethodsAutologous adipose‐derived MSCs (or artificial CSF) were delivered intrathecally, either with single or with repeated injections into the foramen magnum of healthy rabbits and monitored for 4 and 12 weeks, respectively.ResultsRabbits tolerated injections well and no definitive MSC‐related side effects were observed apart from three rabbits that had delayed death secondary to traumatic foramen magnum puncture. Functional assessments and body weights were equivalent between groups. Gross pathology and histology did not reveal any abnormalities or tumor growth. Complete blood count data were normal and there were no differences in CSF interleukin‐6 levels in all groups tested.ConclusionOur data suggest that intrathecal delivery of autologous MSCs is safe in a rabbit model. Data from this study have supported two successful investigational new drug applications to the Food and Drug Administration, resulting in the initiation of two clinical trials using autologous MSCs in amyotrophic lateral sclerosis and multiple system atrophy.

Purpose The purpose of this prospective comparative study was to evaluate the effect of intraoperative platelet‐rich plasma (PRP) injection on the outcomes of patients undergoing hip arthroscopy for labral treatment. Methods During the period from November 2010 through March 2012, all patients undergoing hip arthroscopy for labral tears were considered for this study. The study group received intra‐articular PRP at the end of the operation, and the control group received an intra‐articular injection of 0.25% bupivacaine. Selection for the study group was based on the day of the week on which the patient underwent surgery. The protocol included administration of 4 hip‐specific patient‐reported outcome tools. Patients also reported their pain score on a visual analog scale from 0 to 10. Scores were recorded at the preoperative visit and at 3 months and 2 years postoperatively. Results A minimum of 2 years' follow‐up was available for 306 patients. Thirteen patients (4.2%) underwent conversion to total hip arthroplasty and 24 patients (7.8%) underwent revision hip arthroscopy, which left 91 patients in the study group and 180 patients in the control group. The study group had slightly higher pain scores than the control group (3.4 v 2.5) 2 years after surgery ( P = .005). No difference in pain scores was identified at 3 months postoperatively. The 2‐year modified Harris Hip Score was slightly lower in the study group (78.6) than in the control group (82.6) ( P = .049). No significant difference was observed for the Hip Outcome Score–Activities of Daily Living, Hip Outcome Score–Sport‐Specific Subscale, or Non‐Arthritic Hip Score at any time point. There was no significant difference between groups for conversion to total hip arthroplasty or revision surgery. Conclusions On the basis of the results of this study, intraoperative PRP injection does not appear to improve the clinical results of patients undergoing hip arthroscopy for labral treatment. Level of Evidence Level II, prospective comparative study.

AbstractWith increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimer's Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimer's disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long‐term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimer's Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimer's and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimer's by 2025. This report presents these Workgroup recommendations.

Previous studies have shown that human immunodeficiency virus (HIV) protease cleaves procaspase 8 to a fragment, termed Casp8p41, that lacks caspase activity but nonetheless contributes to T cell apoptosis. Herein, we show that Casp8p41 contains a domain that interacts with the BH3-binding groove of pro-apoptotic Bak to cause Bak oligomerization, Bak-mediated membrane permeabilization, and cell death. Levels of active Bak are higher in HIV-infected T cells that express Casp8p41. Conversely, targeted mutations in the Bak-interacting domain diminish Bak binding and Casp8p41-mediated cell death. Similar mutations in procaspase 8 impair the ability of HIV to kill infected T cells. These observations support a novel paradigm in which HIV converts a normal cellular constituent into a direct activator that functions like a BH3-only protein.

Risk factors contributing to institutionalization after inpatient rehabilitation for people with traumatic brain injury (TBI) have not been well studied and need to be better understood to guide clinicians during rehabilitation. We aimed to develop a prognostic model that could be used at admission to inpatient rehabilitation facilities to predict discharge disposition. The model could be used to provide the interdisciplinary team with information regarding aspects of patients' functioning and/or their living situation that need particular attention during inpatient rehabilitation if institutionalization is to be avoided. The study population included 7219 patients with moderate-severe TBI in the Traumatic Brain Injury Model Systems (TBIMS) National Database enrolled from 2002–2012 who had not been institutionalized prior to injury. Based on institutionalization predictors in other populations, we hypothesized that among people who had lived at a private residence prior to injury, greater dependence in locomotion, bed-chair-wheelchair transfers, bladder and bowel continence, feeding, and comprehension at admission to inpatient rehabilitation programs would predict institutionalization at discharge. Logistic regression was used, with adjustment for demographic factors, proxy measures for TBI severity, and acute-care length-of-stay. C-statistic and predictiveness curves validated a five-variable model. Higher levels of independence in bladder management (adjusted odds ratio [OR], 0.88; 95% CI 0.83, 0.93), bed-chair-wheelchair transfers (OR, 0.81 [95% CI, 0.83–0.93]), and comprehension (OR, 0.78 [95% CI, 0.68, 0.89]) at admission were associated with lower risks of institutionalization on discharge. For every 10-year increment in age was associated with a 1.38 times higher risk for institutionalization (95% CI, 1.29, 1.48) and living alone was associated with a 2.34 times higher risk (95% CI, 1.86, 2.94). The c-statistic was 0.780. We conclude that this simple model can predict risk of institutionalization after inpatient rehabilitation for patients with TBI.

ABSTRACTIntroduction: The aim of this study is to characterize autonomic impairment in motor neuron disease. Methods: Neurological evaluations and autonomic testing were analyzed retrospectively in 132 patients: 86 classic amyotrophic lateral sclerosis (ALS), 36 lower motor neuron (LMN), and 10 upper motor neuron (UMN) predominant disease. Results: One‐third of patients were symptomatic; urinary urgency and constipation were the most frequent symptoms. Increased Composite Autonomic Severity Score (CASS) was present in 75% with mild impairment (CASS 1–3) in 85% and moderate (CASS 4–7) in 15%. The frequencies of testing abnormalities were: sudomotor 46%, cardiovagal 50%, and adrenergic 14%. The UMN group had significantly higher median CASS scores than the classic ALS (P = 0.021) and LMN group (P = 0.018). Conclusions: We found predominantly mild autonomic impairment in ALS patients, with mostly cardiovagal and sudomotor involvement. Moderate autonomic failure occurred in 1 of 7 patients, especially those with an UMN presentation. Patients with selective corticospinal tract involvement may have more impairment of autonomic pathways. Muscle Nerve 51:676–679, 2015

Biomedical scientists can exploit initiatives from U.S. federal regulatory and funding agencies aimed at accelerating clinical translation.

Abstract Background: NPC is endemic to Asia and over 40% of cases harbor PIK3CA amplification. MK2206 is an allosteric AKT inhibitor with activity in NPC in vitro. Methods: Pts who had progressed after palliative chemotherapy (chemo) for metastatic or recurrent NPC, received oral MK-2206 at 200 mg on Days 1, 8, 15 & 22 of each 28-day cycle until disease progression. Plasma samples were collected at serial time points during cycle 1 for EBV DNA analysis, archived tumor samples were collected where feasible. The primary dual endpoints (2-stage design) consisted of RECIST-defined tumor response rate (RR) and 6-month (m) progression-free survival (PFS) rate. Secondary endpoints were overall survival (OS), PFS and adverse events (AEs). Results: Of the 21 pts enrolled, the median age was 47 years (range: 32-67), 91% were male, 81% had prior radiotherapy and 81% had > 1 prior line of palliative chemo. At the time of analysis, 20 out of 21 pts have ended treatment. The best responses were: 1 partial response (PR, 5%) lasting 4 ms; 10 stable disease (SD, 50%), 9 progressive disease (PD, 45%). The 6-m PFS rate was 38.9% (95% CI: 18.1-59.3%) and median PFS was 2.7 ms (95% CI: 0.9-7.2 ms). The 6-m OS rate was 67.9% (95% CI: 41.8-84.1%) and median survival has not been reached. In 7 pts who had SD more than or equal to 6 ms, the duration of treatment ranged from 6.4-13.9 ms. Of the 21 pts evaluable for AEs, 12 pts (57%) had at least one grade 3 AE [[Unable to Display Character: –]] macular rash (6 pts - 29%), dysphagia (2 pts - 10%), hyperglycemia (2 pts - 10%) (see Table 1). The tumor samples of 7 pts were analyzed by FISH; 3 showed PIK3CA amplification, including 1 pt with chromosome 3 polysomy. Amongst these pts, 1 had SD more than 6ms, 1 had SD more than 12 ms, and 1 is still on treatment. Pts who had SD less than 6 m or PD did not have PIK3CA amplification. Conclusions: MK2206 is well tolerated and has signs of activity in unselected pts with NPC. Preliminary results suggest that PIK3CA amplification may be related to prolonged disease stabilization from MK2206, and analysis for other PIK3CA gene alterations in more samples will be undertaken. Result of the plasma EBV DNA result will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B273. Citation Format: Brigette B. Ma, Boon Cher Goh, Wan Teck Lim, Eng Huat Tan, Gilberto de Lima Lopes, Edwin P. Hui, Ann D. King, Kwok Wai Lo, Herbert Loong, Leung Li, Nathan Foster, Michael Kam, Sing Fai Leung, Charles Erlichman, Anthony TC Chan. Multicenter Phase II study of MK-2206 in previously treated patients (pts) with recurrent and metastatic nasopharyngeal carcinoma (NPC): Mayo Clinic Phase II Consortium (Protocol: MC1079). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B273.

SummaryAs invasive mucormycosis (IM) numbers rise, clinicians suspect prior voriconazole worsens IM incidence and severity, and believe combination anti‐fungal therapy improves IM survival. To compare the cumulative incidence (CI), severity and mortality of IM in eras immediately before and after the commercial availability of voriconazole all IM cases from 1995 to 2011 were analysed across four risk‐groups (hematologic/oncologic malignancy (H/O), stem cell transplantation (SCT), solid organ transplantation (SOT) and other), and two eras, E1 (1995–2003) and E2, (2004–2011). Of 101 IM cases, (79 proven, 22 probable): 30 were in E1 (3.3/year) and 71 in E2 (8.9/year). Between eras, the proportion with H/O or SCT rose from 47% to 73%, while ‘other’ dropped from 33% to 11% (P = 0.036). Between eras, the CI of IM did not significantly increase in SCT (P = 0.27) or SOT (P = 0.30), and patterns of anatomic location (P = 0.122) and surgical debridement (P = 0.200) were similar. Significantly more patients received amphotericin‐echinocandin combination therapy in E2 (31% vs. 5%, P = 0.01); however, 90‐day survival did not improve (54% vs. 59%, P = 0.67). Since 2003, the rise of IM reflects increasing numbers at risk, not prior use of voriconazole. Frequent combination of anti‐fungal therapy has not improved survival.

Abstract Recent evidence indicates that sensory and motor changes may precede the cognitive symptoms of Alzheimer's disease (AD) by several years and may signify increased risk of developing AD. Traditionally, sensory and motor dysfunctions in aging and AD have been studied separately. To ascertain the evidence supporting the relationship between age‐related changes in sensory and motor systems and the development of AD and to facilitate communication between several disciplines, the National Institute on Aging held an exploratory workshop titled “Sensory and Motor Dysfunctions in Aging and AD.” The scientific sessions of the workshop focused on age‐related and neuropathologic changes in the olfactory, visual, auditory, and motor systems, followed by extensive discussion and hypothesis generation related to the possible links among sensory, cognitive, and motor domains in aging and AD. Based on the data presented and discussed at this workshop, it is clear that sensory and motor regions of the central nervous system are affected by AD pathology and that interventions targeting amelioration of sensory‐motor deficits in AD may enhance patient function as AD progresses.