Rapid construction of a dendritic cell vaccine through physical perturbation and apoptotic malignant T cell loading

We have demonstrated that adherence and release of monocytes from a plastic surface drives their differentiation into immature dendritic cells (DC,) that can mature further during overnight incubation in the presence of apoptotic malignant T cells. Based on these results, we sought to develop a clinically, practical, rapid means for producing DC loaded with malignant cells. A leukapheresis harvest containing the clonal, leukemic expansion of malignant CD4(+ )T cells was obtained from the blood of patients with cutaneous T cell lymphoma (CTCL). CTCL cells were purified with a CD3-magnetic bead column where CD3 engagement rendered the malignant T cells apoptotic. The monocyte fraction was simultaneously activated by column passage, re-added to the apoptotic CTCL cells and co-cultured overnight. CTCL cell apoptosis, DC differentiation and apoptotic malignant T cell ingestion were measured by immunostaining. The results demonstrate that as monocytes passed through the column matrix, they became activated and differentiated into semi-mature DC expressing significantly increased levels of class II, CD83 and CD86 (markers associated with maturing DC) and reduced expression of the monocyte markers CD14 and CD36. Apoptotic malignant T cells were avidly engulfed by the phagocytic transitioning DC. The addition of supportive cytokines further enhanced the number of DC that contained apoptotic malignant T cells. Functional studies confirmed that column passaged DC increased class II expression as shown by significantly enhanced stimulation in mixed leukocyte culture compared to control monocytes. In addition, DC loaded with apoptotic CTCL cells stimulated an increase in the percentage and absolute number of CD8 T cells compared to co-cultivation with non-loaded DC. After CD8 T cells were stimulated by DC loaded with malignant cells, they mediated increased apoptosis of residual CTCL cells and TNF-α secretion indicating development of enhanced cytolytic function. We report a simple one-step procedure where maturing DC containing apoptotic malignant T cells can be prepared rapidly for potential use in vaccine immunotherapy. Ready access to both the DC and apoptotic cells provided by this system will allow extension to other malignancies through the addition of a variety of apoptotic tumor cells and maturation stimuli

Long term outcomes in men screened for abdominal aortic aneurysm : prospective cohort study

PMID: 22563092 [PubMed - indexed for MEDLINE] PMCID: PMC3344734 Free PMC ArticlePeer reviewedPublisher PD

Clinical features in primary care electronic records before diagnosis of ankylosing spondylitis : a nested case-control study

Background Ankylosing spondylitis (AS) often has a long period from first symptom presentation to diagnosis. We examined the occurrence of symptoms, prescriptions and diagnostic tests in primary care electronic records over time prior to a diagnosis of AS. Methods Nested case-control study using anonymised primary care electronic health records from Scotland. Cases were 74 adults with a first diagnosis of AS between 2000 and 2010. Controls were matched for age, sex and GP practice: (a) 296 randomly selected adults (b) 169 adults whose records contained codes indicating spinal conditions or symptoms. We extracted clinical features (symptoms, AS-related disorders, prescriptions and diagnostic tests). Conditional logistic regression was used to examine the association between clinical features (both individually and in combinations) and diagnosis of AS. We examined the associations between clinical features and diagnosis over time prior to diagnosis. Results Several new composite pointers were predictive of AS: including distinct episodes of axial pain separated by more than 6 months (OR 12.7, 95% CI 4.7 to 34.6); the occurrence of axial pain with and tendon symptoms within the same year (OR 21.7, 95% CI 2.6 to 181.5); and the co-occurrence (within 30 days) of axial pain and a prescription for nonsteroidal anti-inflammatory drug (OR 10.4, 95%CI 4.9 to 22.1). Coded episodes of axial pain increased steadily over the 3 years before diagnosis. In contrast, large joint symptoms and enthesopathy showed little or no time trend prior to diagnosis. Conclusions We identified novel composite pointers to a diagnosis of AS in GP records. These may represent valuable targets for diagnostic support systems

Disease activity in and quality of life of patients with psoriatic arthritis mutilans : the Nordic PAM Study

Objective: To describe the social status and health-related quality of life of patients with psoriatic arthritis mutilans (PAM) in the Nordic countries.Method: Patients with at least one mutilated joint confirmed by radiology were studied. Disease activity involving joints and skin, physician-assessed disease activity, and patient's education and work status were recorded. Data from the 36-item Short Form Health Survey, Health Assessment Questionnaire and Dermatology Life Quality Index questionnaire were gathered and correlated with disease duration, pain, and general well-being (visual analogue scale). The controls were 58 Swedish patients with long-standing psoriatic arthritis sine PAM.Results: Sixty-seven patients were included. Patients with PAM had a protracted disease history (3314years) and disease onset at a relatively early age (30 +/- 12years). Overall inflammatory activity at inclusion was mild to moderate. The mean number of mutilated joints was 8.2 and gross deformity was found in 16% of patients. Forty per cent were treated with biological and 32% with conventional synthetic disease-modifying anti-rheumatic drugs. Forty-two per cent had retired early or were on sick leave. Impaired functional capacity with little or no ability to perform self-care or everyday tasks was reported by 21% of the patients. Patients between 45 and 60years of age reported the most impaired quality of life in comparison to the control group.Conclusion: PAM seriously affects social functioning. Whether early recognition of PAM and new forms of therapy can improve disease outcome and quality of life remains to be studied.Peer reviewe

The invisible maze task (IMT): Interactive exploration of sparse virtual environments to investigate action-driven formation of spatial representations

© Springer Nature Switzerland AG 2018. The neuroscientific study of human navigation has been constrained by the prerequisite of traditional brain imaging studies that require participants to remain stationary. Such imaging approaches neglect a central component that characterizes navigation - the multisensory experience of self-movement. Navigation by active movement through space combines multisensory perception with internally generated self-motion cues. We investigated the spatial microgenesis during free ambulatory exploration of interactive sparse virtual environments using motion capture synchronized to high resolution electroencephalographic (EEG) data as well AS psychometric and self-report measures. In such environments, map-like allocentric representations must be constructed out of transient, egocentric first-person perspective 3-D spatial information. Considering individual differences of spatial learning ability, we studied if changes in exploration behavior coincide with spatial learning of an environment. To this end, we analyzed the quality of sketch maps (a description of spatial learning) that were produced after repeated learning trials for differently complex maze environments. We observed significant changes in active exploration behavior from the first to the last exploration of a maze: a decrease in time spent in the maze predicted an increase in subsequent sketch map quality. Furthermore, individual differences in spatial abilities as well as differences in the level of experienced immersion had an impact on the quality of spatial learning. Our results demonstrate converging evidence of observable behavioral changes associated with spatial learning in a framework that allows the study of cortical dynamics of navigation

Dust devils on Mars: Effects of surface roughness on particle threshold

Abstract not available