Editorial.

Multiple sclerosis (MS) is widely-considered to be the result of an aggressive autoreactive T cell attack on myelin. How these autoimmune responses arise in MS is unclear, but they could result from virus infections. Thus, viral and autoimmune diseases in animals have been used to investigate the possible pathogenic mechanisms operating in MS. The autoimmune model, experimental autoimmune encephalomyelitis, is the most widely-used animal model and has greatly influenced therapeutic approaches targeting autoimmune responses. To investigate demyelination and remyelination in the absence of the adaptive immune response, toxin-induced demyelination models are used. These include using cuprizone, ethidium bromide and lysolecithin to induce myelin damage, which rapidly lead to remyelination when the toxins are withdrawn. The virus models include natural and experimental infections such as canine distemper, visna infection of sheep, and infection of non-human primates. The most commonly used viral models in rodents are Semliki Forest virus and Theilers murine encephalomyelitis virus. The viral and experimental autoimmune encephalomyelitis models have been instrumental in the understanding of how viruses trigger inflammation, demyelination and neurodegeneration in the central nervous system. However, due to complexity of the animal models, pathological mechanisms are also examined in central nervous system cell culture systems including co-cultures, aggregate cultures and brain slice cultures. Here we critically review in vitro and in vivo models used to investigate MS. Since knowledge gained from these models forms the basis for the development of new therapeutic approaches for MS, we address the applicability of the models. Finally, we provide guidance for using and reporting animal studies with the aim of improving translational studies to the clinic.

Over recent years, experimental data on the role of cannabinoids in physiological processes has revealed that there are few areas of physiology where the actions of cannabinoids do not exert some influence, from the control of neuronal signaling to the regulation of bone formation and homeostasis. It is also becoming increasingly clear that many neurological diseases share common mechanisms of neuronal damage and one of primary importance appears to be perturbation of excitatory neuronal signaling resulting in excitotoxic neuronal death. The location of these events and the type of neuronal damage leads to the clinical manifestation of each disease, and to the development of symptoms such as spasticity seen in multiple sclerosis (MS). Cannabinoids can regulate neurotransmitter release and signaling plus elements of oxidative stress that may be neurotoxic in excess. There may a number of neurological diseases such as MS, which should be amenable to cannabinoid therapy, not only for symptom relief but also as neuroprotective strategies to modulate disease progression. Cannabinoids may be particularly attractive as they display low toxicity and with correct dose titration should be well tolerated. In addition, agents that enhance endocannabinoid levels, by inhibition of uptake/degradation, which are already elevated at sites of injury may also be an attractive approach, as it will bring a more targeted strategy of action whilst potentially limiting unwanted psychoactive side effects. Experimental and clinical studies have resulted in the first cannabis-based medicine, Sativex®, being licensed for the treatment of MS spasticity in a number of countries, including the UK.

Both immune-mediated and neurodegenerative processes play a role In the pathogenesis of multiple sclerosis (MS). There is still considerable debate, however, on how to link these two seemingly unrelated elements in disease. It has also remained unclear how the immune system can be involved without harboring any obvious myelin-directed abnormality in MS patients. Here, we propose that the unique properties of a small heat shock protein, HSPB5, can help reconcile the role of the immune system with the neurodegenerative element in MS, and explain the absence of any peripheral immune abnormality in patients. By being selectively induced as a protective stress protein in oligodendrocytes, and subsequently triggering activation of nearby microglia, HSPB5 accumulation translates neurodegenerative signals into a local innate immune response. The immune-regulatory profile of HSPB5-activated microglia, as well as animal model data, indicate that the HSPB5-induced innate response is neuroprotective. However, the presence of pro-inflammatory HSPB5-reactive memory T cells in the human immune repertoire, a unique feature among mammals, can subvert this response. Recruited by the innate response, such T cells respond to the accumulation of HSPB5 by an adaptive immune response, dominated by IFN-g production, that ultimately overwhelms the originally protective microglial response, and culminates in tissue damage. Thus, HSPB5 accumulation caused by neurodegeneration can provoke a destructive local adaptive response of an otherwise normal immune system. This scenario is fully consistent with known causative factors and the pathology of MS, and with the effects of various therapies. It also helps explain why MS develops only in humans.

ABSTRACT: INTRODUCTION: Aboriginal status has been unreliably and incompletely recorded in health and vital registration data collections for the most populous areas of Australia, including NSW where 29\% of Australian Aboriginal people reside. This paper reports an assessment of Aboriginal status recording in NSW cancer registrations and estimates incidence, mortality and survival from cancer in NSW Aboriginal people using multiple imputation of missing Aboriginal status in NSW Central Cancer Registry cancer (CCR) records. METHODS: Logistic regression modelling and multiple imputation were used to assign Aboriginal status to those records of cancer diagnosed from 1999 to 2008 with missing Aboriginality (affecting 12-18\% of NSW cancers registered in this period). Estimates of incidence, mortality and survival from cancer in NSW Aboriginal people were compared with the NSW total population, as standardised incidence and mortality ratios, and with the non-Aboriginal population. RESULTS: Following imputation, 146 (12.2\%) extra cancers in Aboriginal males and 140 (12.5\%) in Aboriginal females were found for 1999-2007. Mean annual cancer incidence in NSW Aboriginal people was estimated to be 660 per 100,000 and 462 per 100,000, 9\% and 6\% higher than all NSW males and females respectively. Mean annual cancer mortality in NSW Aboriginal people was estimated to be 251 per 100,000 in males and 169 per 100,000 in females, 68\% and 73\% higher than for all NSW males and females respectively. Despite similar incidence of localised cancer, mortality from localised cancer in Aboriginal people is significantly higher than in non-Aboriginal people, as is mortality from cancers with regional, distant and unknown degree of spread. Cancer survival in Aboriginal people is significantly lower: 51\% of males and 43\% of females had died of the cancer by 5 years following diagnosis, compared to 36\% and 33\% of non-Aboriginal males and females respectively. CONCLUSION: The present study is the first to produce valid and reliable estimates of cancer incidence, survival and mortality in Australian Aboriginal people from NSW. Despite somewhat higher cancer incidence in Aboriginal than in non-Aboriginal people, substantially higher mortality, and lower survival in Aboriginal people, is only partly explained by more advanced cancer at diagnosis.

Dscam1 potentially encodes 19,008 ectodomains of a cell recognition molecule of the immunoglobulin (Ig) superfamily through alternative splicing. Each ectodomain, comprising a unique combination of three variable (Ig) domains, exhibits isoform-specific homophilic binding in vitro. Although we have proposed that the ability of Dscam1 isoforms to distinguish between one another is crucial for neural circuit assembly, via a process called self-avoidance, whether recognition specificity is essential in vivo has not been addressed. Here we tackle this issue by assessing the function of Dscam1 isoforms with altered binding specificities. We generated pairs of chimeric isoforms that bind to each other (heterophilic) but not to themselves (homophilic). These isoforms failed to support self-avoidance or did so poorly. By contrast, coexpression of complementary isoforms within the same neuron restored self-avoidance. These data establish that recognition between Dscam1 isoforms on neurites of the same cell provides the molecular basis for self-avoidance.

The folding of natural biopolymers into unique three-dimensional structures that determine their function is remarkable considering the vast number of alternative states and requires a large gap in the energy of the functional state compared to the many alternatives. This Perspective explores the implications of this energy gap for computing the structures of naturally occurring biopolymers, designing proteins with new structures and functions, and optimally integrating experiment and computation in these endeavors. Possible parallels between the generation of functional molecules in computational design and natural evolution are highlighted.

BACKGROUND To describe the serial histopathology of intermediate risk stage 3 neuroblastoma after chemotherapy, and correlate with residual mass at therapy completion and outcome. PROCEDURE A retrospective review of intermediate risk stage 3 neuroblastoma patients treated 1989-2005 at Children's Hospital Los Angeles according to CCG 3881 or CCG 3961 protocols was performed, with central review of histopathology, radiology, and surgery. RESULTS Eighteen patients treated per CCG 3881 (n = 9) or CCG 3961 (n = 9), with including 1 (n = 5), 2 (n = 9), ≥ 3 (n = 3), or unknown number (n = 1) of surgical procedures were included. At therapy completion, 10 patients had residual tumor:<10% original size (n = 3),>10% original size (n = 6)(5 MIBG avid; 4 with elevated catecholamines), and CT non-measurable MIBG avid tumor (n = 1). Post-chemotherapy histology showed tumor regression (n = 4); or maturation with (n = 6) or without (n = 2) Schwannian development. Histologic changes correlated with median tumor shrinkage of 80%(regressing tumors) and <25%(maturing tumors). Tumor size increased in one patient with maturing tumor and Schwannian development. Overall survival was 100%. CONCLUSION Post-chemotherapy histopathology of intermediate risk stage 3 neuroblastoma was characterized by regression or maturation. Persisting residual and maturing tumors were not associated with tumor progression, despite MIBG uptake and/or elevated catecholamines, supporting observation only. Histopathology should be obtained in future studies to confirm these findings, and guide length of chemotherapy.

In multiple sclerosis (MS), a chronic inflammatory relapsing demyelinating disease, failure to control or repair damage leads to progressive neurological dysfunction and neurodegeneration. Implantation of neural stem cells (NSCs) has been shown to promote repair and functional recovery in the acute experimental autoimmune encephalomyelitis (EAE) animal model for MS; the major therapeutic mechanism of these NSCs appeared to be immune regulation. In the present study, we examined the efficacy of intraventricularly injected NSCs in chronic relapsing experimental autoimmune encephalomyelitis (CREAE), the animal disease model which is widely accepted to mimic most closely recurrent inflammatory demyelination lesions as observed in relapsing-remitting MS. In addition, we assessed whether priming these NSCs to become oligodendrocyte precursor cells (OPCs) by transient overexpression of Olig2 would further promote functional recovery, e.g. by contributing to actual remyelination.Upon injection at the onset of the acute phase or the relapse phase of CREAE, NSCs as well as Olig2-NSCs directly migrated towards active lesions in the spinal cord as visualized by in vivo bioluminescence and biofluorescence imaging and once in the spinal cord the majority of Olig2-NSCs, in contrast to NSCs, differentiated into OPCs. The survival of Olig2-NSCs was significantly higher than that of injected control NSCs, which remained undifferentiated. Nevertheless both Olig2-NSCs and NSC significantly reduced the clinical signs of acute and relapsing disease, and, in case of Olig2-NSCs, even completely abrogated relapsing disease when administered early after onset of acute disease. We provide the first evidence that NSCS and in particular NSC-derived OPCs (Olig2-NSCs) ameliorate established chronic relapsing EAE in mice. Our experimental data in established neurological disease in mice indicates that such therapy may be effective in relapsing-remitting MS preventing chronic progressive disease.