The development of training in the casework method for social workers in two European countries, France and Belgium, during the period 1950-1960

Thesis (M.S.)--Boston Universit

The Role of T Lymphocytes in the Pathogenesis of Hu Antibody Associated Paraneoplastic Neurological Syndromes

Paraneoplastic neurological syndromes (PNS) result from damage or dysfunction of the nervous system that is by definition not caused by tumor cell infiltration, infection, ischemia, metabolic and nutritional deficits, surgery or other forms of tumor treatment. Immunologic factors appear important in the pathogenesis of PNS because antineuronal antibodies against nervous system antigens have been defined for many of these disorders. The immunologic response is elicited by the ectopic expression of neuronal antigens by the tumor. Expression of these so-called ‘onconeural’ antigens is limited to the tumor and the nervous system. At the time of presentation of the neurological symptoms, most patients have not yet been diagnosed with cancer. Detection of paraneoplastic antibodies is extremely helpful in diagnosing an otherwise unexplained, and often rapidly progressive neurological syndrome as paraneoplastic. In addition, the paraneoplastic antibodies may also direct the search for an underlying neoplasm. The diagnosis and clinical management of PNS are reviewed in chapter 2. One of the most frequently involved solid tumors in PNS is small cell lung cancer (SCLC) and approximately 50% of patients with PNS and SCLC have high-titer Hu antibodies. This thesis focused on PNS that are associated with Hu-antibodies (Hu-PNS)

Disease activity in primary progressive multiple sclerosis:a systematic review and meta-analysis

Background: Disease activity in multiple sclerosis (MS) is defined as presence of relapses, gadolinium enhancing lesions and/or new or enlarging lesions on MRI. It is associated with efficacy of immunomodulating therapies (IMTs) in primary progressive MS (PPMS). However, a thorough review on disease activity in PPMS is lacking. In relapsing remitting MS, the prevalence of activity decreases in more contemporary cohorts. For PPMS, this is unknown. Aim: To review disease activity in PPMS cohorts and identify its predictors. Methods: A systematic search in EMBASE, MEDLINE, Web of science Core Collection, COCHRANE CENTRAL register of trials, and GOOGLE SCHOLAR was performed. Keywords included PPMS, inflammation, and synonyms. We included original studies with predefined available data, extracted cohort characteristics and disease activity outcomes and performed meta-regression analyses. Results: We included 34 articles describing 7,109 people with PPMS (pwPPMS). The weighted estimated proportion of pwPPMS with overall disease activity was 26.8% (95% CI 20.6–34.0%). A lower age at inclusion predicted higher disease activity (OR 0.91, p = 0.031). Radiological activity (31.9%) was more frequent than relapses (9.2%), and was predicted by longer follow-up duration (OR 1.27, p = 0.033). Year of publication was not correlated with disease activity. Conclusion: Inflammatory disease activity is common in PPMS and has remained stable over the last decades. Age and follow-up duration predict disease activity, advocating prolonged monitoring of young pwPPMS to evaluate potential IMT benefits

Ocrelizumab associates with reduced cerebrospinal fluid B and CD20^dim CD4⁺ T cells in primary progressive multiple sclerosis

The anti-CD20 monoclonal antibody ocrelizumab reduces disability progression in primary progressive multiple sclerosis. CD20 is a prototypical B-cell marker; however, subpopulations of CD4 + and CD8 + T cells in peripheral blood and cerebrospinal fluid also express low levels of CD20 (CD20 dim). Therefore, direct targeting and depletion of these CD20 dim T-cell subpopulations may contribute to the therapeutic effect of ocrelizumab. The aim of this observational cohort study was to compare CD20 + B-cell and CD20 dim T-cell distributions between peripheral blood and cerebrospinal fluid of ocrelizumab-treated or ocrelizumab-untreated people with primary progressive multiple sclerosis. Ocrelizumab treatment was associated with depletion of circulating B cells and CD20 dim CD4 + and CD20 dim CD8 + T cells (P &lt; 0.0001, P = 0.0016 and P = 0.0008, respectively) but, in cerebrospinal fluid, only with lower proportions of B cells and CD20 dim memory CD4 + T cells (P &lt; 0.0001 and P = 0.0043, respectively). The proportional prevalence of cerebrospinal fluid CD20 dim memory CD8 + T cells was not significantly reduced (P = 0.1333). Only in cerebrospinal fluid, the proportions of CD20 dim cells within CD4 + and not CD8 + T cells positive for CCR5, CCR6 and CXCR3 were reduced in ocrelizumab-treated participants. The proportion of CD20 dim CD4 + T cells and abundance of CD4 + relative to CD8 + T cells in cerebrospinal fluid correlated positively with age (R = 0.6799, P = 0.0150) and Age-Related Multiple Sclerosis Severity score (R = 0.8087, P = 0.0014), respectively. We conclude that, in contrast to cerebrospinal fluid CD20 dim CD8 + T cells, B cells and CD20 dim CD4 + T cells are reduced in cerebrospinal fluid of people with primary progressive multiple sclerosis with an ocrelizumab-associated depletion of circulating B cells and CD20 dim T cells. Therefore, these cells are likely to contribute to the therapeutic effects of ocrelizumab in people with primary progressive multiple sclerosis.</p

Deep sleep maintains learning efficiency of the human brain

It is hypothesized that deep sleep is essential for restoring the brain's capacity to learn efficiently, especially in regions heavily activated during the day. However, causal evidence in humans has been lacking due to the inability to sleep deprive one target area while keeping the natural sleep pattern intact. Here we introduce a novel approach to focally perturb deep sleep in motor cortex, and investigate the consequences on behavioural and neurophysiological markers of neuroplasticity arising from dedicated motor practice. We show that the capacity to undergo neuroplastic changes is reduced by wakefulness but restored during unperturbed sleep. This restorative process is markedly attenuated when slow waves are selectively perturbed in motor cortex, demonstrating that deep sleep is a requirement for maintaining sustainable learning efficiency

Pathologically confirmed autoimmune encephalitis in suspected Creutzfeldt-Jakob disease

Objective: To determine the clinical features and presence in CSF of antineuronal antibodies in patients with pathologically proven autoimmune encephalitis derived from a cohort of patients with suspected Creutzfeldt-Jakob disease (CJD). Methods: The Dutch Surveillance Centre for Prion Diseases performed 384 autopsies on patients with suspected CJD over a 14-year period (1998-2011). Clinical information was collected from treating physicians. Antineuronal antibodies were tested in CSF obtained postmortem by immunohistochemistry on fresh frozen rat brain sections, by Luminex assay for the presence of wellcharacterized onconeural antibodies, and by cell-based assays for antibodies against NMDAR, GABABR1/2, GABAAR GLUR1/2, LGI1, Caspr2, and DPPX. Results: In 203 patients, a diagnosis of definite CJD was made, while in 181 a variety of other conditions were diagnosed, mainly neurodegenerative. In 22 of these 181, the neuropathologist diagnosed autoimmune encephalitis. One patient was excluded because of lack of clinical information. Inflammator

No evidence for circulating HuD-specific CD8+ T cells in patients with paraneoplastic neurological syndromes and Hu antibodies

Aim: In paraneoplastic neurological syndromes (PNS) associated with small cell lung cancer (SCLC) and Hu antibodies (Hu-PNS), Hu antigens expressed by the tumour hypothetically trigger an immune response that also reacts with Hu antigens in the nervous system, resulting in tumour suppression and neuronal damage. To gain more insight into the hypothesized CD8+T cell-mediated immune pathogenesis of these syndromes, we searched for circulating HuD-specific CD8+T cells in a large cohort of Hu-PNS patients and controls. Patients and methods: Blood was tested from 43 Hu-PNS patients, 31 Hu antibody negativ

Tolerance to the Neuron-Specific Paraneoplastic HuD Antigen

Experiments dating back to the 1940's have led to the hypothesis that the brain is an immunologically privileged site, shielding its antigens from immune recognition. The paraneoplastic Hu syndrome provides a powerful paradigm for addressing this hypothesis; it is believed to develop because small cell lung cancers (SCLC) express the neuron-specific Hu protein. This leads to an Hu-specific tumor immune response that can develop into an autoimmune attack against neurons, presumably when immune privilege in the brain is breached. Interestingly, all SCLC express the onconeural HuD antigen, and clinically useful tumor immune responses can be detected in up to 20% of patients, yet the paraneoplastic neurologic syndrome is extremely rare. We found that HuD-specific CD8+ T cells are normally present in the mouse T cell repertoire, but are not expanded upon immunization, although they can be detected after in vitro expansion. In contrast, HuD-specific T cells could be directly activated in HuD null mice, without the need for in vitro expansion. Taken together, these results demonstrate robust tolerance to the neuronal HuD antigen in vivo, and suggest a re-evaluation of the current concept of immune privilege in the brain