Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma.

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL. SIGNIFICANCE: Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival. This article is highlighted in the In This Issue feature, p. 85.

Psychological Profiles and Clinical Clusters of Patients Diagnosed With Functional Neurological Disorder.

Our understanding about underlying mechanisms leading to Functional Neurological Disorders (FND) has changed in recent years. While in the past these disorders were presumed to be solely due to psychological issues we know now that their development is dependent on complex interactions between biological, psychological and social factors. We present an analysis of clinical presentations and psychological profiles of patients who were seen in our FND outpatient clinic over 3 years. We aim to review the prevalence of common symptoms in the patients seen within our clinic, and to identify any common psychological or psychiatric profiles that differentiated these symptom groups. This may help to elucidate underlying mechanisms leading to the development of functional symptoms and identify the predisposing, triggering and perpetuation factors.

Functional neurological disorders: effective teaching for health professionals.

OBJECTIVES: To provide an outline for the delivery of an educational course or lecture about functional neurological disorders (FND) that is directed towards health professionals with varying clinical knowledge and to highlight the educational efficacy that can be derived from a well-designed educational platform. METHOD: Through multidisciplinary collaboration, a course designed to develop the skills for diagnosis and management of FND was created. Elements essential to the delivery of education are: (A) knowledge creation; (B) facilitating multidisciplinary cross-pollination; (C) listening to patients' experiences; (D) communication skills practice; (E) case studies; (F) discipline specific mentoring; (G) establishing and addressing participant learning goals and (H) developing collegial and referral networks. Changes in participants' knowledge and clinical practice were assessed via anonymous questionnaires before and after the course. RESULTS: Dramatically improved knowledge and confidence in assessment and management of people with FND has been found both immediately following the course as well as on 6-month follow-up. CONCLUSION: It is possible to make real change in the understanding and management of medical and allied health clinicians working with people with FND with a low-cost intervention. Also, the development of educational networks and multidisciplinary collaboration can lead to the creation of therapeutic platforms for the diagnosis, management and advocacy of this patient group.

Fibrinogen binding is affected by amino acid substitutions in C-terminal repeat region of fibronectin binding protein A.

Fibronectin-binding protein A (FnBPA), a protein displayed on the outer surface of Staphylococcus aureus, has a structured A-domain that binds fibrinogen (Fg) and a disordered repeat-region that binds fibronectin (Fn). Amino acid substitutions in Fn-binding repeats (FnBRs) have previously been linked to cardiovascular infection in humans. Here we used microtiter and atomic force microscopy (AFM) to investigate adhesion by variants of full-length FnBPA covalently anchored in the outer cell wall of Lactococcus lactis, a Gram-positive surrogate that otherwise lacks adhesins to mammalian ligands. Fn adhesion increased in five of seven FnBPA variants under static conditions. The bond targeting Fn increased its strength with load under mechanical dissociation. Substitutions extended bond lifetime (1/koff) up to 2.1 times for FnBPA-Fn. Weaker adhesion was observed for Fg in all FnBPA variants tested with microtiter. However, mechanical dissociation with AFM showed significantly increased tensile strength for Fg interacting with the E652D/H782Q variant. This is consistent with a force-induced mechanism and suggests that the dock, lock, and latch (DLL) mechanism is favored for Fg-binding under mechanical stress. Collectively, these experiments reveal that FnBPA exhibits bimodal, ligand-dependent adhesive behavior. Amino acid substitutions in the repeat-region of FnBPA impact binding to both ligands. This was unexpected for Fg since all variants have the same A-domain sequence, and the Fg-binding site is distant from the repeat region. This indicates that FnBRs may fold back on the A-domain in a way that impacts the DLL binding mechanism for Fg.

Evaluation of a caregiver education program to support memory and communication in dementia: a controlled pretest-posttest study with nursing home staff.

BACKGROUND: There is a need for simple multimedia training programs designed to upskill the dementia care workforce. A DVD-based training program entitled RECAPS and MESSAGE has been designed to provide caregivers with strategies to support memory and communication in people with dementia. OBJECTIVES: The aims of this study were: (1) to evaluate the effects of the RECAPS and MESSAGE training on knowledge of support strategies, and caregiver satisfaction, in nursing home care staff, and (2) to evaluate staff opinion of the training. DESIGN: A multi-centre controlled pretest-posttest trial was conducted between June 2009 and January 2010, with baseline, immediately post-training and 3-month follow-up assessment. SETTING: Four nursing homes in Queensland, Australia. PARTICIPANTS: All care staff were invited to participate. Of the 68 participants who entered the study, 52 (37 training participants and 15 controls) completed outcome measures at baseline and 3-month follow-up. 63.5% of participants were nursing assistants, 25% were qualified nurses and 11.5% were recreational/activities officers. METHODS: The training and control groups were compared on the following outcomes: (1) knowledge of memory and communication support strategies, and (2) caregiver satisfaction. In the training group, the immediate effects of training on knowledge, and the effects of role (nurse, nursing assistant, recreational staff) on both outcome measures, were also examined. Staff opinion of the training was assessed immediately post-training and at 3-month follow-up. RESULTS: The training group showed a significant improvement in knowledge of support strategies from baseline to immediately post-training (p=0.001). Comparison of the training and control groups revealed a significant increase in knowledge for the training group (p=0.011), but not for the control group (p=0.33), between baseline and 3-month follow-up. Examination of caregiver satisfaction by care staff role in the training group revealed that only the qualified nurses showed higher levels of caregiver satisfaction at 3-month follow-up (p=0.013). Staff rated the training positively both for usefulness and applicability. CONCLUSION: The RECAPS and MESSAGE training improved nursing home care staff's knowledge of support strategies for memory and communication, and gains were maintained at 3-month follow-up. Moreover, the training was well received by staff.

Memory and communication support in dementia: research-based strategies for caregivers.

BACKGROUND: Difficulties with memory and communication are prominent and distressing features of dementia which impact on the person with dementia and contribute to caregiver stress and burden. There is a need to provide caregivers with strategies to support and maximize memory and communication abilities in people with dementia. In this project, a team of clinicians, researchers and educators in neuropsychology, psychogeriatrics, nursing and speech pathology translated research-based knowledge from these fields into a program of practical strategies for everyday use by family and professional caregivers. METHODS: From the available research evidence, the project team identified compensatory or facilitative strategies to assist with common areas of difficulty, and structured these under the mnemonics RECAPS (for memory) and MESSAGE (for communication). This information was adapted for presentation in a DVD-based education program in accordance with known characteristics of effective caregiver education. RESULTS: The resultant DVD comprises (1) information on the nature and importance of memory and communication in everyday life; (2) explanations of common patterns of difficulty and preserved ability in memory and communication across the stages of dementia; (3) acted vignettes demonstrating the strategies, based on authentic samples of speech in dementia; and (4) scenarios to prompt the viewer to consider the benefits of using the strategies. CONCLUSION: Using a knowledge-translation framework, information and strategies can be provided to family and professional caregivers to help them optimize residual memory and communication in people with dementia. Future development of the materials, incorporating consumer feedback, will focus on methods for enabling wider dissemination.

ERP measures indicate both attention and working memory encoding decrements in aging.

We investigated age-related attention and encoding deficits, and their possible interaction, by analyzing visual event-related potentials from young and older adults during a modified Sternberg word recognition task. Young adults performed more accurately, albeit not significantly so. P1 latency was shorter in young adults and correlated negatively with task accuracy (with age partialed out). These data support proposals that P1 indexes attentional suppression, which is less efficient in older adults. N1 was larger in older adults but did not correlate with accuracy. Young adults had higher P2 amplitudes and P2 latency correlated with accuracy (age partialed), supporting the view that semantic operations during encoding are affected by aging. These data indicate that attention (P1) and encoding (P2) decrements may contribute to memory or related cognitive decrements in aging, and P1 and P2 latency measures from appropriate paradigms may be salient ERP markers of these decrements.

Theta oscillations are affected by amnestic mild cognitive impairment and cognitive load.

Amnestic mild cognitive impairment (aMCI) is classified primarily via substantial episodic memory deficits in the absence of a dementia diagnosis. To investigate the potential neurophysiological correlates of such deficits we compared QEEG power between 12 participants with aMCI and 12 healthy matched controls. EEG was acquired during performance of a modified Sternberg word recognition task with low and high memory load conditions. While recognition accuracy of aMCI participants was lower than that of controls, this difference was not significant. Nevertheless the aMCI group demonstrated significantly lower theta power at a number of electrode sites and significant correlations were observed between power at these sites and neuropsychological assessment scores. Furthermore in the aMCI sample only, theta power was significantly lower under high versus low memory load. Given current interpretations of the neural generator(s), as well as the role(s), of theta oscillations in cognitive processes, the present data indicate that aMCI may be associated with disruptions in the operation of neurocognitive networks (e.g., MTL-neocortical), particularly under high cognitive load.