The Transatlantic HbA1c gap: differences in glycaemic control across the lifespan between people included in the US T1D Exchange Registry and those included in the German/Austrian DPV registry.

AIM: To compare HbA1c levels across the lifespan in people with type 1 diabetes in the USA with those in Germany/Austria, and to examine potential differences in HbA1c levels between sexes, insulin delivery methods and minority status. METHODS: Data were extracted from the US T1D Exchange Registry (n=18 381 participants from 73 sites) and from the German/Austrian Prospective Diabetes Follow-up Registry, the DPV (n=32 643 participants from 362 sites). Mean HbA1c was calculated for each year of age for individuals aged ≤25 years, and at 2-year age intervals for individuals aged >25 years. Curves for mean HbA1c by age were estimated using locally weighted scatterplot smoothing. HbA1c differences between registries, sexes, insulin delivery methods, and minority status were assessed by age group using multiple linear regression. RESULTS: In both registries, mean HbA1c increased by ~11 mmol/mol (1.0%) between the ages of 9 and 18 years, although at quite different absolute levels: from 66 mmol/mol (8.2%) to 77 mmol/mol (9.2%) in the T1D Exchange Registry, and from 56 mmol/mol (7.3%) to 66 mmol/mol (8.2%) in the DPV. Sex differences were observed in the DPV only. In the T1D Exchange Registry, injection users had higher mean HbA1c than pump users across the lifespan, whereas in the DPV higher HbA1c levels in injection users were observed in the age groups 6 to <12 years, 12 to <18 years, and 30 to <50 years (P < 0.001). Minority status was significantly associated with higher HbA1c in most age groups in both registries. CONCLUSIONS: Significant differences in HbA1c were noted between the USA and Germany/Austria, with disparities more pronounced in early childhood through to young adulthood. Further studies should identify causes for these disparities.

Time spent outside of target glucose range for young children with type 1 diabetes: a continuous glucose monitor study.

AIM: To assess the associations between demographic and clinical characteristics and sensor glucose metrics in young children with type 1 diabetes, using masked, continuous glucose monitoring data from children aged 2 to < 8 years. RESEARCH DESIGN AND METHODS: The analysis included 143 children across 14 sites in the USA, enrolled in a separate clinical trial. Eligibility criteria were: age 2 to <8 years; type 1 diabetes duration ≥3 months; no continuous glucose monitoring use for past 30 days; and HbA1c concentration 53 to <86 mmol/mol (7.0 to <10.0%). All participants wore masked continuous glucose monitors up to 14 days. RESULTS: On average, participants spent the majority (13 h) of the day in hyperglycaemia (>10.0 mmol/l) and a median of ~1 h/day in hypoglycaemia (<3.9 mmol/l). Participants with minority race/ethnicity and higher parent education levels spent more time in target range, 3.9-10.0 mmol/l, and less time in hyperglycaemia. More time in hypoglycaemia was associated with minority race/ethnicity and younger age at diagnosis. Continuous glucose monitoring metrics were similar in pump and injection users. CONCLUSIONS: Given that both hypo- and hyperglycaemia negatively impact neurocognitive development, strategies to increase time in target glucose range for young children are needed.

Olfactory gene expression in migrating adult sockeye salmon Oncorhynchus nerka.

Expression of 12 olfactory genes was analysed in adult sockeye salmon Oncorhynchus nerka nearing spawning grounds and O. nerka that had strayed from their natal migration route. Variation was found in six of these genes, all of which were olfc olfactory receptors and had lower expression levels in salmon nearing spawning grounds. The results may reflect decreased sensitivity to natal water olfactory cues as these fish are no longer seeking the correct migratory route. The expression of olfactory genes during the olfactory-mediated spawning migration of Pacific salmon Oncorhynchus spp. is largely unexplored and these findings demonstrate a link between migratory behaviours and olfactory plasticity that provides a basis for future molecular research on salmon homing.

Are low sun exposure and/or vitamin D risk factors for type 1 diabetes?

The global variation in type 1 diabetes (T1D) incidence rates is one of the most significant observed for any non-communicable disease. Geographical patterns in incidence suggest that low sun exposure may contribute to the wide disparity, with incidence rates generally increasing with distance from the Equator. T1D development is associated with hyperactivity of the adaptive immune system leading to autoimmune destruction of insulin-secreting pancreatic ß cells. Both exposure to ultraviolet radiation (UVR) and vitamin D, with their known immunosuppressive effects, have the potential to delay or inhibit the disease. Efforts to confirm the role of UVR by vitamin D dependent and independent pathways in the pathogenesis of T1D have been challenged by inconsistent results among studies. Human observational studies and animal and in vitro experiments indicate that at least some of the benefits of sun exposure come from improved vitamin D status. There is no evidence of benefit for T1D risk of vitamin D supplementation during pregnancy at current recommended levels (400 IU per day); but some evidence supports that higher sun exposure and/or vitamin D sufficiency in pregnancy, or supplementation in early life, decreases T1D risk. Further research is required to confirm an association between UVR exposure and T1D and clarify the mechanisms involved.

A survey of microparasites present in adult migrating Chinook salmon (Oncorhynchus tshawytscha) in south-western British Columbia determined by high-throughput quantitative polymerase chain reaction.

Microparasites play an important role in the demography, ecology and evolution of Pacific salmonids. As salmon stocks continue to decline and the impacts of global climate change on fish populations become apparent, a greater understanding of microparasites in wild salmon populations is warranted. We used high-throughput, quantitative PCR (HT-qRT-PCR) to rapidly screen 82 adult Chinook salmon from five geographically or genetically distinct groups (mostly returning to tributaries of the Fraser River) for 45 microparasite taxa. We detected 20 microparasite species, four of which have not previously been documented in Chinook salmon, and four of which have not been previously detected in any salmonids in the Fraser River. Comparisons of microparasite load to blood plasma variables revealed some positive associations between Flavobacterium psychrophilum, Cryptobia salmositica and Ceratonova shasta and physiological indices suggestive of morbidity. We include a comparison of our findings for each microparasite taxa with previous knowledge of its distribution in British Columbia.

Glycaemic control of Type 1 diabetes in clinical practice early in the 21st century: an international comparison.

AIMS: Improving glycaemic control in people with Type 1 diabetes is known to reduce complications. Our aim was to compare glycaemic control among people with Type 1 diabetes using data gathered in regional or national registries. METHODS: Data were obtained for children and/or adults with Type 1 diabetes from the following countries (or regions): Western Australia, Austria, Denmark, England, Champagne-Ardenne (France), Germany, Epirus, Thessaly and Thessaloniki (Greece), Galway (Ireland), several Italian regions, Latvia, Rotterdam (The Netherlands), Otago (New Zealand), Norway, Northern Ireland, Scotland, Sweden, Volyn (Ukraine), USA and Wales) from population or clinic-based registries. The sample size with available data varied from 355 to 173 880. Proportions with HbA1c < 58 mmol/mol (< 7.5%) and ≥ 75 mmol/mol (≥ 9.0%) were compared by age and sex. RESULTS: Data were available for 324 501 people. The proportions with HbA1c 58 mmol/mol (< 7.5%) varied from 15.7% to 46.4% among 44 058 people aged < 15 years, from 8.9% to 49.5% among 50 766 people aged 15-24 years and from 20.5% to 53.6% among 229 677 people aged ≥ 25 years. Sex differences in glycaemic control were small. Proportions of people using insulin pumps varied between the 12 sources with data available. CONCLUSION: These results suggest that there are substantial variations in glycaemic control among people with Type 1 diabetes between the data sources and that there is room for improvement in all populations, especially in young adults.

Adolescent intermittent alcohol exposure: persistence of structural and functional hippocampal abnormalities into adulthood.

BACKGROUND: Human adolescence is a crucial stage of neurological development during which ethanol (EtOH) consumption is often at its highest. Alcohol abuse during adolescence may render individuals at heightened risk for subsequent alcohol abuse disorders, cognitive dysfunction, or other neurological impairments by irreversibly altering long-term brain function. To test this possibility, we modeled adolescent alcohol abuse (i.e., intermittent EtOH exposure during adolescence [AIE]) in rats to determine whether adolescent exposure to alcohol leads to long-term structural and functional changes that are manifested in adult neuronal circuitry. METHODS: We specifically focused on hippocampal area CA1, a brain region associated with learning and memory. Using electrophysiological, immunohistochemical, and neuroanatomical approaches, we measured post-AIE changes in synaptic plasticity, dendritic spine morphology, and synaptic structure in adulthood. RESULTS: We found that AIE-pretreated adult rats manifest robust long-term potentiation, induced at stimulus intensities lower than those required in controls, suggesting a state of enhanced synaptic plasticity. Moreover, AIE resulted in an increased number of dendritic spines with characteristics typical of immaturity. Immunohistochemistry-based analysis of synaptic structures indicated a significant decrease in the number of co-localized pre- and postsynaptic puncta. This decrease is driven by an overall decrease in 2 postsynaptic density proteins, PSD-95 and SAP102. CONCLUSIONS: Taken together, these findings reveal that repeated alcohol exposure during adolescence results in enduring structural and functional abnormalities in the hippocampus. These synaptic changes in the hippocampal circuits may help to explain learning-related behavioral changes in adult animals preexposed to AIE.

Facing warm temperatures during migration: cardiac mRNA responses of two adult Oncorhynchus nerka populations to warming and swimming challenges.

The main findings of the current study were that exposing adult sockeye salmon Onchorhynchus nerka to a warm temperature that they regularly encounter during their river migration induced a heat shock response at an mRNA level, and this response was exacerbated with forced swimming. Similar to the heat shock response, increased immune defence-related responses were also observed after warm temperature treatment and with a swimming challenge in two different populations (Chilko and Nechako), but with some important differences. Microarray analyses revealed that 347 genes were differentially expressed between the cold (12-13° C) and warm (18-19° C) treated fish, with stress response (GO:0006950) and response to fungus (GO:0009620) elevated with warm treatment, while expression for genes involved in oxidative phosphorylation (GO:0006119) and electron transport chain (GO:0022900) elevated for cold-treated fish. Analysis of single genes with real-time quantitative PCR revealed that temperature had the most significant effect on mRNA expression levels, with swimming and population having secondary influences. Warm temperature treatment for the Chilko population induced expression of heat shock protein (hsp) 90α, hsp90ß and hsp30 as well as interferon-inducible protein. The Nechako population, which is known to have a narrower thermal tolerance window than the Chilko population, showed even more pronounced stress responses to the warm treatment and there was significant interaction between population and temperature treatment for hsp90ß expression. Moreover, significant interactions were noted between temperature treatment and swimming challenge for hsp90α and hsp30, and while swimming challenge alone increased expression of these hsps, the expression levels were significantly elevated in warm-treated fish swum to exhaustion. In conclusion, it seems that adult O. nerka currently encounter conditions that induce several cellular defence mechanisms during their once-in-the-lifetime migration. As river temperatures continue to increase, it remains to be seen whether or not these cellular defences provide sufficient protection for all O. nerka populations.

Dead fish swimming: a review of research on the early migration and high premature mortality in adult Fraser River sockeye salmon Oncorhynchus nerka.

Adult sockeye salmon Oncorhynchus nerka destined for the Fraser River, British Columbia are some of the most economically important populations but changes in the timing of their homeward migration have led to management challenges and conservation concerns. After a directed migration from the open ocean to the coast, this group historically would mill just off shore for 3-6 weeks prior to migrating up the Fraser River. This milling behaviour changed abruptly in 1995 and thereafter, decreasing to only a few days in some years (termed early migration), with dramatic consequences that have necessitated risk-averse management strategies. Early migrating fish consistently suffer extremely high mortality (exceeding 90% in some years) during freshwater migration and on spawning grounds prior to spawning. This synthesis examines multidisciplinary, collaborative research aimed at understanding what triggers early migration, why it results in high mortality, and how fisheries managers can utilize these scientific results. Tissue analyses from thousands of O. nerka captured along their migration trajectory from ocean to spawning grounds, including hundreds that were tracked with biotelemetry, have revealed that early migrants are more reproductively advanced and ill-prepared for osmoregulatory transition upon their entry into fresh water. Gene array profiles indicate that many early migrants are also immunocompromised and stressed, carrying a genomic profile consistent with a viral infection. The causes of these physiological changes are still under investigation. Early migration brings O. nerka into the river when it is 3-6° C warmer than historical norms, which for some late-run populations approaches or exceeds their critical maxima leading to the collapse of metabolic and cardiac scope, and mortality. As peak spawning dates have not changed, the surviving early migrants tend to mill in warm lakes near to spawning areas. These results in the accumulation of many more thermal units and longer exposures to freshwater diseases and parasites compared to fish that delay freshwater entry by milling in the cool ocean environment. Experiments have confirmed that thermally driven processes are a primary cause of mortality for early-entry migrants. The Fraser River late-run O. nerka early migration phenomenon illustrates the complex links that exist between salmonid physiology, behaviour and environment and the pivotal role that water temperature can have on population-specific migration survival.

Temporal changes in blood variables during final maturation and senescence in male sockeye salmon Oncorhynchus nerka: reduced osmoregulatory ability can predict mortality.

This study is the first to characterize temporal changes in blood chemistry of individuals from one population of male sockeye salmon Oncorhynchus nerka during the final 6 weeks of sexual maturation and senescence in the freshwater stage of their spawning migration. Fish that died before the start of their historic mean spawning period (c. 5 November) were characterized by a 20-40% decrease in plasma osmolality, chloride and sodium, probably representing a complete loss of osmoregulatory ability. As fish became moribund, they were further characterized by elevated levels of plasma cortisol, lactate and potassium. Regressions between time to death and plasma chloride (8 October: P < 0·001; 15 October: P < 0·001) indicate that plasma chloride was a strong predictor of longevity in O. nerka. That major plasma ion levels started to decline 2-10 days (mean of 6 days) before fish became moribund, and before other stress, metabolic or reproductive hormone variables started to change, suggests that a dysfunctional osmoregulatory system may initiate rapid senescence and influence other physiological changes (i.e. elevated stress and collapsed reproductive hormones) which occur as O. nerka die on spawning grounds.

Handling, infectious agents and physiological condition influence survival and post-release behaviour in migratory adult coho salmon after experimental displacement.

For Pacific salmon captured and released by fisheries, post-release behaviour and survival may be influenced by their health and condition at time of capture. We sought to characterize the interactions between infectious agent burden, fish immune and stress physiology and fisheries stressors to investigate the potential for capture-mediated pathogen-induced mortality in adult coho salmon Oncorhynchus kisutch. We used radio-telemetry paired with high-throughput qPCR of non-lethal gill biopsies for infectious agents and host biomarkers from 200 tagged fish experimentally displaced and exposed to various experimental fisheries treatments (gill net entanglement, recreational angling and recreational angling with air exposure vs. non-sampled control). We characterized relationships among post-release behaviour and survival, infectious agent presence and loads, physiological parameters and transcription profiles of stress and immune genes. All infectious agents detected were endemic and in loads consistent with previous adult Pacific salmon monitoring. Individuals exposed to fisheries treatments were less likely to reach spawning habitat compared to controls, and handling duration independent of fisheries gear had a negative effect on survival. High infectious agent burden was associated with accelerated migration initiation post-release, revealing behavioural plasticity in response to deteriorating condition in this semelparous species. Prevalence and load of infectious agents increased post-migration as well as transcription signatures reflected changes in immune and stress profiles consistent with senescence. Results from this study further our understanding of factors associated with fisheries that increase risk of post-release mortality and characterize some physiological mechanisms that underpin migratory behaviour.

Evidence of a hydraulically challenging reach serving as a barrier for the upstream migration of infection-burdened adult steelhead.

Anadromous fishes such as steelhead trout, Oncorhynchus mykiss, are exposed to a suite of infectious agents and migratory challenges during their freshwater migrations. We assessed infectious agent load and richness and immune system gene expression in gill tissue of Bulkley River (British Columbia, CA) steelhead captured at and upstream of a migratory barrier to evaluate whether infectious burdens impacted migration success. We further considered the potential influences of water temperature, sex and fish size on host infectious agents and transcription profiles. There were eight infectious agents detected in steelhead gill tissue, with high prevalence of the bacteria Candidatus Branchiomonas cysticola (80%) and Flavobacterium psychrophilum (95%) and the microparasite Sphaerothecum destruens (53%). Fish sampled at the falls had significantly greater relative loads of Ca. B. cysticola and F. psychrophilum, higher infectious agent richness and differential gene expression compared to fish captured upstream. Flavobacterium psychrophilum was only associated with immune gene expression (particularly humoral immunity) of fish sampled at the falls, while water temperature was positively correlated with genes involved in the complement system, metabolic stress and oxidative stress for fish captured upstream. This work highlights interesting differences in agent-host interactions across fisheries and suggests that hydraulic barriers may reduce the passage of fish with the heaviest infectious agent burdens, emphasizing the selective role of areas of difficult passage. Further, this work expands our knowledge of infectious agent prevalence in wild salmonids and provides insight into the relationships between infectious agents and host physiology.

Differentiating salmon populations at broad and fine geographical scales with microsatellites and single nucleotide polymorphisms.

Single nucleotide polymorphisms (SNPs) are appealing genetic markers due to several beneficial attributes, but uncertainty remains about how many of these bi-allelic markers are necessary to have sufficient power to differentiate populations, a task now generally accomplished with highly polymorphic microsatellite markers. In this study, we tested the utility of 37 SNPs and 13 microsatellites for differentiating 29 broadly distributed populations of Chinook salmon (n = 2783). Information content of all loci was determined by In and G'(ST), and the top 12 markers ranked by In were microsatellites, but the 6 highest, and 7 of the top 10 G'(ST) ranked markers, were SNPs. The mean ratio of random SNPs to random microsatellites ranged from 3.9 to 4.1, but this ratio was consistently reduced when only the most informative loci were included. Individual assignment test accuracy was higher for microsatellites (73.1%) than SNPs (66.6%), and pooling all 50 markers provided the highest accuracy (83.2%). When marker types were combined, as few as 15 of the top ranked loci provided higher assignment accuracy than either microsatellites or SNPs alone. Neighbour-joining dendrograms revealed similar clustering patterns and pairwise tests of population differentiation had nearly identical results with each suite of markers. Statistical tests and simulations indicated that closely related populations were better differentiated by microsatellites than SNPs. Our results indicate that both types of markers are likely to be useful in population genetics studies and that, in some cases, a combination of SNPs and microsatellites may be the most effective suite of loci.

Neonatal withdrawal syndrome following in utero exposure to paroxetine, clonazepam and olanzapine.

We describe a full-term infant with failed respiratory effort and decerebrate posturing following in utero exposure to paroxetine. All signs and symptoms associated with the paroxetine exposure were resolved by the second day of life. Upon discharge, the infant revealed a normal neurodevelopmental examination.

Meconium exposure and autism risk.

OBJECTIVE: This study aims to determine whether fetal meconium passage is associated with autism. STUDY DESIGN: This retrospective birth cohort analysis of 9 945 896 children born in California 1991 to 2008 linked discharge diagnosis and procedure codes for prenatal stressors, meconium-stained amniotic fluid (MSAF) and meconium aspiration syndrome (MAS) with autism diagnoses for 47 277 children through 2012. We assessed the relative risk of autism by meconium status using logistic regression, adjusting for demographic and clinical features. RESULTS: Children exposed to meconium (MSAF and MAS) were more likely to be diagnosed with autism in comparison with unexposed children (0.60% and 0.52%, vs 0.47%, respectively). In adjusted analyses, there was a small increase in autism risk associated with MSAF exposure (adjusted relative risk (aRR) 1.18, 95% confidence interval (CI) 1.12 to 1.25), and a marginal association that failed to achieve significance between MAS and autism (aRR 1.08, 95% CI 0.98 to 1.20). CONCLUSION: Resuscitation of neonates with respiratory compromise from in utero meconium exposure may mitigate long-term neurodevelopmental damage.

Matrix metalloproteinase upregulation in chronic inflammatory demyelinating polyneuropathy and nonsystemic vasculitic neuropathy.

OBJECTIVE: To determine the expression pattern and cellular source of matrix metalloproteinases (MMPs) in chronic inflammatory demyelinating polyneuropathy (CIDP) and nonsystemic vasculitic neuropathy (NSVN). BACKGROUND: MMPs are endopeptidases involved in tissue destruction and infiltration by immune cells in multiple sclerosis and Guillain-Barré syndrome. Enzyme inhibitors of MMPs attenuate clinical symptoms in corresponding animal models of these diseases. MMP inhibition may therefore be a novel approach for the treatment of CIDP and NSVN. However, the spectrum of MMPs expressed in chronic inflammatory neuropathies has not been established. METHODS: The expression of MMP-2, MMP-3, MMP-7, and MMP-9 in T cells, macrophages, and stromal cells in CIDP, NSVN, and noninflammatory neuropathies (NIN) was quantitated by immunohistochemistry. Results were correlated with clinical and electrophysiologic findings. RESULTS: The production of MMP-2 and MMP-9 is increased in nerve tissue in CIDP and NSVN compared with NIN. T cells are the predominant source of MMP-2 and MMP-9 in CIDP and NSVN, whereas macrophages contribute only to a minor extent. Stromal cells of the perineurium/epineurium are an additional source of MMP-2 in NSVN, but not in CIDP. Expression of MMP-3 and MMP-7 was not detectable in CIDP or NSVN. Expression of MMP-2 and MMP-9 did not correlate with clinical disease activity and electrophysiologic measurements. CONCLUSIONS: The upregulation of MMP-2 and MMP-9 is a specific feature of CIDP and NSVN, and selective inhibitors of these enzymes could be used to prevent inflammatory tissue damage. The similar increase of MMP-2 and MMP-9 in both demyelinating (CIDP) and nondemyelinating (NSVN) neuropathies raises doubts about whether MMPs play a primary role in demyelination.

A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are produced.

Alzheimer's disease (AD) is the commonest form of adult onset dementia and is characterised neuropathologically by the accumulation of plaques containing beta-amyloid (A beta) fibrils, reactive astrocytes, activated microglia, and leukocytes. A beta plays a role in the pathology of AD by directly causing neuronal cytotoxicity and stimulating microglia to secrete cytokines and reactive oxygen species (ROS) which also damage neurons. Here, we demonstrate that A beta activates astrocytes and oligodendrocytes (the most common cell types in the brain) to produce chemokines, in particular MCP-1 and RANTES, which serve as potent in vitro microglial and macrophage chemoattractants. Furthermore, we have shown that A beta activates astrocytes to upregulate pro-inflammatory cytokine expression and enhances the production of ROS. We propose therefore that A beta-mediated astrocyte activation initiates an inflammatory cascade which could be targeted for therapeutic intervention in AD.

Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview.

The matrix metalloproteinases (MMPs) are a family of at least 14 zinc-dependent enzymes which are known to degrade the protein components of extracellular matrix. In addition, MMPs and related enzymes can also process a number of cell surface cytokines, receptors, and other soluble proteins. In particular we have shown that the release of the pro-inflammatory cytokine, tumor necrosis factor-alpha, from its membrane-bound precursor is an MMP-dependent process. MMPs are expressed by the inflammatory cells which are associated with CNS lesions in animal models of multiple sclerosis (MS) and in tissue from patients with the disease. MMP expression will contribute to the tissue destruction and inflammation in MS. Drugs which inhibit MMP activity are effective in animal models of MS and may prove to be useful therapies in the clinic.

Matrix metalloproteinase expression during experimental autoimmune encephalomyelitis and effects of a combined matrix metalloproteinase and tumour necrosis factor-alpha inhibitor.

Matrix metalloproteinases (MMPs) are a large family of Zn2+ endopeptidases that are expressed in inflammatory conditions and are capable of degrading connective tissue macromolecules. MMP-like enzymes are also involved in the processing of a variety of cell surface molecules including the pro-inflammatory cytokine TNF-alpha. MMPs and TNF-alpha have both been implicated in the pathology associated with neuro-inflammatory diseases (NIDs), particularly multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). We have shown that BB-1101, a broad spectrum hydroxamic acid-based combined inhibitor of MMP activity and TNF processing, reduces the clinical signs and weight loss in an acute EAE model in Lewis rats. However, little is known about which MMPs are involved in the neuroinflammatory process. In order to determine the optimum inhibitory profile for an MMP inhibitor in the treatment of NID, we investigated the profile of MMP expression and activity during EAE. The development of disease symptoms was associated with a 3-fold increase in MMP activity in the cerebrospinal fluid (CSF), which could be inhibited by treatment with BB-1101, and an increase in 92 kDa gelatinase activity detected by gelatin substrate zymography. Quantitative PCR analysis of normal and EAE spinal cord revealed the expression of at least seven MMPs. Of these, matrilysin showed the most significant change, being elevated over 500 fold with onset of clinical symptoms and peaking at maximum disease severity. Of the other six MMPs detected, 92 kDa gelatinase showed a modest 5 fold increase which peaked at the onset of clinical signs and then declined during the most severe phase of the disease. Matrilysin was localised by immunohistochemistry to the invading macrophages within the inflammatory lesions of the spinal cord. Matrilysin's potent broad spectrum proteolytic activity and its localisation to inflammatory lesions in the CNS suggest this enzyme could be particularly involved in the pathological processes associated with neuro-inflammatory disease.