Rationale for cytotoxic monoclonal antibodies in MS.

Monoclonal antibodies (MAbs) have been used to treat human disease for over 20 years, and have found a range of applications, predominantly in inflammatory and neoplastic disorders. They are attractive therapies due to their unique specificity and capacity for production on an industrial scale. Cytotoxic MAbs, those that trigger lysis of their cellular target, were first used to probe experimental allergic encephalomyelitis, the standard animal model of MS.

Notes on the kidney and its diseases for the neurologist.

To save their patients from dialysis and transplantation, neurologists need simply remain alert to the possibility of renal failure, particularly in the context of systemic disease, diabetes, sepsis and drugs. Of the numerous territories shared by our respective specialities, we outline a pragmatic approach to the diagnosis and treatment of the vasculitides, underpinned by knowing which questions to ask, equally importantly when to ask them, and in the art of obtaining a tissue diagnosis. We consider the current evolving trial evidence that directs the usage of a growing arsenal of therapies in the induction and maintenance stages of vasculitis treatment, and extend this consideration to Lupus and Sjogren's.

Deletion of p37Ing1 in mice reveals a p53-independent role for Ing1 in the suppression of cell proliferation, apoptosis, and tumorigenesis.

ING proteins have been proposed to alter chromatin structure and gene transcription to regulate numerous aspects of cell physiology, including cell growth, senescence, stress response, apoptosis, and transformation. ING1, the founding member of the inhibitor of growth family, encodes p37(Ing1), a plant homeodomain (PHD) protein that interacts with the p53 tumor suppressor protein and seems to be a critical cofactor in p53-mediated regulation of cell growth and apoptosis. In this study, we have generated and analyzed p37(Ing1)-deficient mice and primary cells to further explore the role of Ing1 in the regulation of cell growth and p53 activity.

Thermal decomposition kinetics of hydrazinium cerium 2,3-Pyrazinedicarboxylate hydrate: a new precursor for CeO2.

The thermal decomposition kinetics of N(2)H(5)[Ce(pyrazine-2,3-dicarboxylate)(2)(H(2)O)] (Ce-P) have been studied by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), for the first time; TGA analysis reveals an oxidative decomposition process yielding CeO(2) as the final product with an activation energy of approximately 160 kJ mol(-1). This complex may be used as a precursor to fine particle cerium oxides due to its low temperature of decomposition.

Mutation of the SNF2 family member Chd2 affects mouse development and survival.

The chromodomain helicase DNA-binding domain (Chd) proteins belong to the SNF2-like family of ATPases that function in chromatin remodeling and assembly. These proteins are characterized by the presence of tandem chromodomains and are further subdivided based on the presence or absence of additional structural motifs. The Chd1-Chd2 subfamily is distinguished by the presence of a DNA-binding domain that recognizes AT-rich sequence.

An investigation of auto-reactivity after head injury.

Murine models of CNS injury show auto-reactive T cell responses directed at myelin antigens, associated with improved neuronal survival and functional recovery. This pilot study shows, for the first time, that similar immune responses against myelin occur in human traumatic brain injury (TBI), with an expansion of lymphocytes recognising myelin basic protein observed in 40% of patients studied. "Reactive" patients did not have greater contusion volume on imaging, but were younger than the "unreactive" subgroup and tended towards a more favorable outcome.

Dehydroepiandrosterone replacement in patients with Addison's disease has a bimodal effect on regulatory (CD4+CD25hi and CD4+FoxP3+) T cells.

Oral replacement of the near-total deficiency of dehydroepiandrosterone (DHEA) in patients with Addison's disease (adrenal insufficiency) enhances mood and well-being and reduces fatigue. We studied the immunological effects of 12 wk of oral DHEA treatment in ten patients with Addison's disease receiving their normal mineralo- and glucocorticoid hormone replacement. We found that baseline circulating regulatory T cells were reduced in Addison's disease patients compared to controls, a hitherto unrecognised defect in this disorder.

Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis.

Following lymphocyte depletion, homeostatic mechanisms drive the reconstitution of lymphocytes. We prospectively studied this process in 16 patients for 1 year after a single pulse of treatment with Campath-1H, a humanised anti-CD52 monoclonal antibody. We observed two phases of lymphocyte reconstitution.

The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy.

From 1991-2002, we treated 58 patients with multiple sclerosis (MS) using the humanised monoclonal antibody, Campath-1H, which causes prolonged T lymphocyte depletion. Clinical and surrogate markers of inflammation were suppressed. In both the relapsing-remitting (RR) and secondary progressive (SP) stages of the illness, Campath-1H reduced the annual relapse rate (from 2.

Rapidly reversible dementia in cerebral amyloid inflammatory vasculopathy.

This report discusses a biopsy proven case of cerebral amyloid angiopathy, with additional prominent vascular inflammatory features, characterized by a rapidly progressive dementia and leukoencephalopathy, where the clinical and radiological abnormalities resolved rapidly with minimal therapeutic intervention. We propose the term cerebral amyloid inflammatory vasculopathy (CAIV) to describe this condition.

Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue.

Wnt5a is a member of the Wnt family of secreted glycoproteins that play essential organizing roles in development. Similar to other Wnt members, Wnt5a can upregulate cell proliferation and has been proposed to have oncogenic function. Here we report that Wnt5a signals through the noncanonical Wnt/Ca++ pathway to suppress cyclin D1 expression and negatively regulate B cell proliferation in a cell-autonomous manner.

Decreased iNOS synthesis mediates dexamethasone-induced protection of neurons from inflammatory injury in vitro.

Brain inflammation is accompanied by transection of axons and death of neurons in the acute lesions of multiple sclerosis. We explored mechanisms of inflammatory damage to neurons in vitro using cocultures of rat embryonal cortical neurons with microglia activated by interferon-gamma (IFNgamma) and lipopolysaccharide (LPS). Previously, we have demonstrated that microglia are highly toxic to neurons and that nitric oxide (NO) derived from inducible nitric oxide synthase (iNOS) is necessary and sufficient to mediate this toxicity.

Informed choice in cancer pain: empowering the patient.

Cancer and palliative care service users can often feel isolated and disempowered. (Tower, 1999). Physical changes, medical interventions and pain can mean that they no longer feel in control of their bodies or their futures.

Multiple sclerosis.

Multiple sclerosis is the prototype inflammatory autoimmune disorder of the central nervous system and, with a lifetime risk of one in 400, potentially the most common cause of neurological disability in young adults. As with all complex traits, the disorder results from an interplay between as yet unidentified environmental factors and susceptibility genes. Together, these factors trigger a cascade of events, involving engagement of the immune system, acute inflammatory injury of axons and glia, recovery of function and structural repair, post-inflammatory gliosis, and neurodegeneration.

No association between multiple sclerosis and the Notch3 gene responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

The clinical and radiological overlap between multiple sclerosis and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; MIM 125310) raises the possibility of diagnostic confusion and suggests that pleiotropic effects of the Notch3 gene might include influencing susceptibility to multiple sclerosis. To investigate these possibilities three microsatellites markers closely flanking the Notch 3 gene in 745 simplex families with multiple sclerosis were genotyped and exon 3 and exon 4 of the gene were directly sequenced in a subset of the index members from these families (n=93). No evidence for association was found in any of the three markers and none of the commoner mutations causing CADASIL were found in the sequenced patients.