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Purpose of Review: This overview of the history of diagnosis and treatment of multiple sclerosis serves as an introduction to the rich history of multiple sclerosis, and shows we are on a continuum of incremental advances that date back centuries., Recent Findings: The current understanding of MS demonstrates a dramatic series of advances and this brief historical overview will provide some context for these discoveries. Although cases we would now recognize as multiple sclerosis can be found in older literature and diaries, the contribution of Jean-Martin Charcot at the Salpêtrière in Paris in 1868 was to frame the clinical and pathological features of a disorder he called la sclérose en plaque disséminées. Soon after, reports came from many countries. Over the next half-century, the diagnosis was a clinical conclusion with no confirmatory tests. Some CSF and evoked potential tests later helped but it remained for the MRI imaging and oligoclonal banding to substantially aid the clinical diagnosis. It is tempting to think that therapy is new in MS, but in previous centuries, hundreds of drugs, procedures, and surgeries were applied to patients with MS, many more than we use today. It remained for the development of the randomized clinical trial to show which therapies were beneficial and safe. Everything changed in 1993 when the first of a long list of new therapies was approved, therapies that were shown to alter the activity and outcome of the disease., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Statistically robust monitoring of threatened populations is essential for effective conservation management because the population trend data that monitoring generates is often used to make decisions about when and how to take action. Despite representing the highest proportion of threatened animals globally, the development of best practice methods for monitoring populations of threatened insects is relatively uncommon. Traditionally, population trend data for the Nationally Endangered New Zealand grasshopper Brachaspis robustus has been determined by counting all adults and nymphs seen on a single ~1.5 km transect searched once annually. This method lacks spatial and temporal replication, both of which are essential to overcome detection errors in highly cryptic species like B. robustus. It also provides no information about changes in the grasshopper's distribution throughout its range. Here, we design and test new population density and site occupancy monitoring protocols by comparing a) comprehensive plot and transect searches at one site and b) transect searches at two sites representing two different habitats (gravel road and natural riverbed) occupied by the species across its remaining range. Using power analyses, we determined a) the number of transects, b) the number of repeated visits and c) the grasshopper demographic to count to accurately detect long term change in relative population density. To inform a monitoring protocol design to track trends in grasshopper distribution, we estimated the probability of detecting an individual with respect to a) search area, b) weather and c) the grasshopper demographic counted at each of the two sites. Density estimates from plots and transects did not differ significantly. Population density monitoring was found to be most informative when large adult females present in early summer were used to index population size. To detect a significant change in relative density with power > 0.8 at the gravel road habitat, at least seventeen spatial replicates (transects) and four temporal replicates (visits) were required. Density estimates at the natural braided river site performed poorly and likely require a much higher survey effort. Detection of grasshopper presence was highest (pg > 0.6) using a 100 m x 1 m transect at both sites in February under optimal (no cloud) conditions. At least three visits to a transect should be conducted per season for distribution monitoring. Monitoring protocols that inform the management of threatened species are crucial for better understanding and mitigation of the current global trends of insect decline. This study provides an exemplar of how appropriate monitoring protocols can be developed for threatened insect species., Competing Interests: The authors have declared that no competing interests exist.

Summary: The 1917 Halifax Explosion was an unfortunate but predictable tragedy, given the sea traffic and munitions cargo, resulting in sudden large-scale damage and catastrophic injuries, with 1950 dead and 8000 injured. Although generous support was received from the United States, the bulk of the medical work was undertaken using local resources through an immediate, massive, centrally coordinated medical response. The incredible care provided 100 years ago by these Canadian physicians, nurses and students is often forgotten, but deserves attention. The local medical response to the 1917 disaster is an early example of coordinated mass casualty relief, the first in Canada, and remains relevant to modern disaster preparedness planning. This commentary has an appendix, available at canjsurg.ca/016317-a1.

Introduction: Multiple sclerosis (MS) is a chronic disease of the central nervous system. Estimates of MS natural history (NH) disability progression speed from clinical observations vary worldwide. This may reflect, in part, variance in censoring-bias) (missing observations) and assumptions about when irreversible disability progression events occurred. We test whether estimates of progression speed which assume midpoint survival time at irreversible disability endpoints are significantly faster than estimates which assume maximum survival time, and are more stable across study groups and time periods., Methods: Our Nova Scotia NH study population includes 2,240 definite relapsing-onset multiple sclerosis (R-MS) natural history patients with 18,078 Expanded Disability Status Scale (EDSS) clinical observations in study period 1979-2010. Progression speed is measured by rate-of-change in range EDSS 0-6 and by survival time at irreversible endpoints EDSS 1-9. Midpoint censoring-bias-reduction methods are applied to clinical observations., Findings: Typical EDSS increase per year in range EDSS 0-6, assuming midpoint survival time, is estimated to be 0.168 for all R-MS, 0.204 for eventually-DMD-treated patients and 0.155 for never-DMD-treated patients. Estimates assuming midpoint rather than maximum survival time are significantly faster: 16% faster for all R-MS natural history patients, 6% faster for eventually-DMD-treated patients, and 21% faster for never-DMD-treated patients. The variability of estimates across study groups and time periods decreased when midpoint survival time was assumed., Conclusions: Estimates of typical disease progression speed from 1979-2010 Nova Scotia clinical observations are sensitive to censoring-bias and to analysts' survival time assumptions. Censoring-bias-adjusted estimates of typical natural history disability progression speed in relapsing-onset multiple sclerosis patients are significantly faster, and less variable within and across study groups and time periods, than unadjusted estimates, and are, arguably, more relevant for various stakeholders. The application of censoring-bias-reduction methods to other multiple sclerosis clinical databases may reduce variability in estimates of disability progression speed worldwide.

Exposure to environmental estrogens (xenoestrogens) may play a causal role in the increased breast cancer incidence which has been observed in Europe and the US over the last 50 years. The xenoestrogen bisphenol A (BPA) leaches from plastic food/beverage containers and dental materials. Fetal exposure to BPA induces preneoplastic and neoplastic lesions in the adult rat mammary gland. Previous results suggest that BPA acts through the estrogen receptors which are detected exclusively in the mesenchyme during the exposure period by directly altering gene expression, leading to alterations of the reciprocal interactions between mesenchyme and epithelium. This initiates a long sequence of altered morphogenetic events leading to neoplastic transformation. Additionally, BPA induces epigenetic changes in some tissues. To explore this mechanism in the mammary gland, Wistar-Furth rats were exposed subcutaneously via osmotic pumps to vehicle or 250 µg BPA/kg BW/day, a dose that induced ductal carcinomas in situ. Females exposed from gestational day 9 to postnatal day (PND) 1 were sacrificed at PND4, PND21 and at first estrus after PND50. Genomic DNA (gDNA) was isolated from the mammary tissue and immuno-precipitated using anti-5-methylcytosine antibodies. Detection and quantification of gDNA methylation status using the Nimblegen ChIP array revealed 7412 differentially methylated gDNA segments (out of 58207 segments), with the majority of changes occurring at PND21. Transcriptomal analysis revealed that the majority of gene expression differences between BPA- and vehicle-treated animals were observed later (PND50). BPA exposure resulted in higher levels of pro-activation histone H3K4 trimethylation at the transcriptional initiation site of the alpha-lactalbumin gene at PND4, concomitantly enhancing mRNA expression of this gene. These results show that fetal BPA exposure triggers changes in the postnatal and adult mammary gland epigenome and alters gene expression patterns. These events may contribute to the development of pre-neoplastic and neoplastic lesions that manifest during adulthood.

Methods: The nine hole peg test (9HPT) is an emerging outcome measure in clinical trials in multiple sclerosis (MS). In this study we investigated how performance on the 9HPT at baseline is related to annualized direct MS related cost., Methods: We enrolled patients with a definite diagnosis of MS from two Canadian MS centers. 9HPT and demographic information were recorded at baseline, and patients prospectively recorded all MS related costs for 6months. Costs were compared among five groups according to the baseline 9HPT, and we built a multiple linear regression model including cost (dependent variable) and 9HPT at baseline, age, disease duration, sex and disease course (independent predictor variables)., Results: We analyzed data from 298 patients. Cost significantly increased with increasing 9HPT scores (p<0.0001), with the costs for health care providers, changes to the home or car and long-term care dominating in the most disabled patient groups. The 9HPT score was a significant predictor of cost in the regression model (p=0.006)., Conclusion: Performance on the 9HPT is closely related to cost. Our data add another aspect of patient relevance to using the 9HPT as an outcome measure in clinical trials., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Understanding the direct and indirect effects of elevated [CO2 ] and temperature on insect herbivores and how these factors interact are essential to predict ecosystem-level responses to climate change scenarios. In three concurrent glasshouse experiments, we measured both the individual and interactive effects of elevated [CO2 ] and temperature on foliar quality. We also assessed the interactions between their direct and plant-mediated effects on the development of an insect herbivore of eucalypts. Eucalyptus tereticornis saplings were grown at ambient or elevated [CO2 ] (400 and 650 μmol mol(-1) respectively) and ambient or elevated ( + 4 °C) temperature for 10 months. Doratifera quadriguttata (Lepidoptera: Limacodidae) larvae were feeding directly on these trees, on their excised leaves in a separate glasshouse, or on excised field-grown leaves within the temperature and [CO2 ] controlled glasshouse. To allow insect gender to be determined and to ensure that any sex-specific developmental differences could be distinguished from treatment effects, insect development time and consumption were measured from egg hatch to pupation. No direct [CO2 ] effects on insects were observed. Elevated temperature accelerated larval development, but did not affect leaf consumption. Elevated [CO2 ] and temperature independently reduced foliar quality, slowing larval development and increasing consumption. Simultaneously increasing both [CO2 ] and temperature reduced these shifts in foliar quality, and negative effects on larval performance were subsequently ameliorated. Negative nutritional effects of elevated [CO2 ] and temperature were also independently outweighed by the direct positive effect of elevated temperature on larvae. Rising [CO2 ] and temperature are thus predicted to have interactive effects on foliar quality that affect eucalypt-feeding insects. However, the ecological consequences of these interactions will depend on the magnitude of concurrent temperature rise and its direct effects on insect physiology and feeding behaviour., (© 2013 Blackwell Publishing Ltd.)

Both atmospheric [CO2] and average surface temperatures are predicted to increase with potentially different, additive or opposing, effects on leaf quality and insect herbivore activity. Few studies have directly measured the interactive effects of concurrent changes in [CO2] and temperature on insect herbivores. None have done so over the entire developmental period of a tree-feeding insect, and none have compared responses to low pre-industrial [CO2] and present day [CO2] to estimate responses to future increases. Eucalypt herbivores may be particularly sensitive to climate-driven shifts in plant chemistry, as eucalypt foliage is naturally low in [N]. In this study, we assessed the development of the eucalypt herbivore Doratifera quadriguttata exposed concurrently to variable [CO2] (290, 400, 650 μmol mol(-1)) and temperature (ambient, ambient +4 °C) on glasshouse-grown Eucalyptus tereticornis. Overall, insects performed best on foliage grown at pre-industrial [CO2], indicating that modern insect herbivores have already experienced nutritional shifts since industrialisation. Rising [CO2] increased specific leaf mass and leaf carbohydrate concentration, subsequently reducing leaf [N]. Lower leaf [N] induced compensatory feeding and impeded insect performance, particularly by prolonging larval development. Importantly, elevated temperature dampened the negative effects of rising [CO2] on larval performance. Therefore, rising [CO2] over the past 200 years may have reduced forage quality for eucalypt insects, but concurrent temperature increases may have partially compensated for this, and may continue to do so in the future. These results highlight the importance of assessing plant-insect interactions within the context of multiple climate-change factors because of the interactive and potentially opposing effects of different factors within and between trophic levels.

In 1930 there were many conflicting views on the cause, incidence, precipitating factors, inheritance and treatment of multiple sclerosis (MS). A young, London neurologist summarized the state of understanding of the disease with his personal view of many of the uncertain areas, and clarified the thinking for the neurological community at that time. Although his later career was influential in many fields of medicine, and his personal influence was extraordinary in many areas as an author, educator, administrator, opinion leader and historian, his review was an important milestone in the history of MS.

Randomized controlled trials have demonstrated the efficacy of disease-modifying drugs (DMDs) in persons with relapsing-remitting multiple sclerosis (MS) and secondary progressive MS with superimposed relapses. However, these brief studies of selected patients have focused mainly on reducing attacks and must be complemented by evaluations in 'realworld' clinical settings to establish the effectiveness of DMD programs in slowing disease progression and to inform health policy and program decision-making. We assessed the effectiveness of DMDs as administered in a comprehensive publicly funded drug insurance program that provides DMDs to a geographically defined population of MS patients who meet specific eligibility criteria. Data from 1752 MS patients (10,312 assessments) seen between 1980 and 2004 at a regional MS Clinic serving the entire population of Nova Scotia, Canada were analysed. Using survival methods we observed a statistically significant reduction in disease progression to specific Expanded Disability Status Scale endpoints following the introduction of this program. Subgroup analyses of patients eligible for treatment using hierarchical linear regression methods also suggested that disease progression was slowed in patients treated with the first DMD prescribed. These findings provide evidence supporting DMD program effectiveness that can be used to inform the broader implementation of such programs.

The first illustration of multiple sclerosis (MS) was by a young Scottish physician and artist, Dr Robert Carswell. Recognized as a talented illustrator by his teachers, he was encouraged to create an anatomy and pathology atlas. He spent years in the hospitals and mortuaries of Paris and Lyon painting watercolours and pen and ink drawings of patients and post mortem preparations. Of the 1034 paintings, 99 are of the brain and spinal cord and Plate 4, figure 4.4 in the atlas (Figure 2), is of MS. Carswell indicated he saw two examples of this pathology, but had not examined either patient, but illustrated one of them. We know little about the clinical history other than that the patient was paralyzed. About 200 of the atlases were printed, and it is still regarded as one of the greatest and most beautiful of all medical books. Carswell was appointed as the first Professor of Anatomy at the North London Hospital, later renamed the University College Hospital UK, where the original copy of his great atlas is archived. Due to ill health he resigned after a few years to reside in the healthier air outside Brussels, Belgium. He was appointed physician to King Leopold, but was also noted for his care of the poor. Queen Victoria knighted him for his care of King Louis Philippe of France when he was in exile. Although English journals did not note his passing at the age of 64 years, his great atlas remains as his memorial.

Background: Our objective was to assess the histological changes in mammary glands of the female Wistar-Furth rat as a result of low dose exposure to N-nitrosomethylurea (NMU)., Methods: Groups of 30-40 virgin female rats of between 49-58 days old received a single injection of 10, 20, 30 or 50 mg NMU/kg body weight (BW). A group of 10 control rats received 0.9% NaCl solution only. The formation of palpable mammary gland tumors was assessed weekly and, upon sacrifice at 12, 22 and 25-30 weeks after treatment, we performed a comprehensive histological analysis of all mammary gland lesions and tumors., Results: Alongside the predicted increase in tumor number and decrease in tumor latency with increasing NMU dose, we observed a number of microscopic lesions and other epithelial abnormalities in the mammary glands for all NMU doses. Two types of non-neoplastic histological changes were observed in rats exposed to 10 or 20 mg NMU/kg BW: namely, (i) an increase in the number of acinar structures often accompanied by secretion into the lumen which is normally associated with pregnancy and lactation, and (ii) an increase in the number of epithelial cells sloughed into the lumen of the epithelial ducts., Conclusion: This study establishes a baseline for low-dose exposure and defines the histological features in the mammary gland resulting from NMU exposure. Furthermore, this system provides an ideal platform for evaluating the relative susceptibility of animals protected from, or predisposed to, developing cancer through environmental influences.

For centuries, it was recognised that there was a condition characterised by episodic and progressive neurological deterioration, classified as 'paraplegia'. Some early cases of 'paraplegia' have been described in sufficient detail to recognise a condition resembling what we now call multiple sclerosis and these cast an interesting light on the approach to therapy before the disease had a name. Multiple sclerosis was differentiated and 'framed' as a separate identifiable entity by von Frerichs, Vulpian, Charcot and others in the mid-nineteenth century. Once framed by its pathology, clinical picture, course and prognosis, cases were diagnosed by others around the world. As knowledge of the disease increased, theories of cause and approaches to treatment increased so that a review in 1935 covered 158 treatments used in MS. There were subsequent waves of therapies including anticoagulants, antibiotics, histamine desensitisation, various diets, vaccines and anti-cancer agents, as well as numerous claims of 'cures'. After the 1960s the methodology for carrying out randomised clinical trials became better defined, aided by improved disease classification and disability scales. As data accumulated, theories were tested to account for observations of genetic influences, environmental factors, geographical variations, infections and immunological changes. The development of multiple sclerosis societies advanced research and public education and changed attitudes towards the disease. At the same time, attitudes of physicians towards management of people with multiple sclerosis changed. In the last fifty years, the major advances have been in basic research to elucidate the mechanisms and processes underlying the disease, the development of imaging techniques (MRI) and the development of immunomodulatory drugs which, for the first time, are altering the outcome of the disease. We have now entered the therapeutic era of multiple sclerosis, with continual major advances bringing hope and benefit to people with multiple sclerosis.

To overcome the chemical and metabolic instability of the secondary fatty acyl residues in the AGP class of lipid A mimetics, the secondary ether lipid analogs of the potent TLR4 agonist CRX-527 (2) and TLR4 antagonist CRX-526 (3) were synthesized and evaluated along with their ester counterparts for agonist/antagonist activity in both in vitro and in vivo models. Like CRX-527, the secondary ether lipid 4 showed potent agonist activity in both murine and human models. Ether lipid 5, on the other hand, showed potent TLR4 antagonist activity similar to CRX-526 in human cell assays, but did not display any antagonist activity in murine models and, in fact, was weakly agonistic. Glycolipids 2, 4, and 5 were synthesized via a new highly convergent method utilizing a common advanced intermediate strategy. A new method for preparing (R)-3-alkyloxytetradecanoic acids, a key component of ether lipids 4 and 5, is also described.

An efficient and readily modifiable synthesis of GEX1A/herboxidiene/TAN-1609 ( 1) was developed. This modular synthesis featured a Suzuki coupling to install the conjugated diene and a Ru-catalyzed lactonization and Roush crotylation to construct the functionalized tetrahydropyran moiety. Myers' alkylation, cross-metathesis, and Keck crotylation were employed for assembly of the biologically essential side-chain domain.

Objective: Benefits from interferon beta (IFNbeta treatment in patients with multiple sclerosis are affected by many factors, including sustained clinical efficacy, acceptable tolerability, adherence to therapy, and the development of neutralizing antibodies (NAbs). The Prospective and Retrospective Long-Term Observational Study of Avonex and Rebif (PROOF) was designed to compare the relative efficacy and tolerability of the two IFNbeta-1a products for up to 5 years., Methods: PROOF compared the relative efficacy and tolerability of intramuscular (IM) IFNbeta-1a (Avonex) 30 microg once weekly (n = 69) and subcutaneous (SC) IFNbeta-1a (Rebif) 44 microg three times per week (n = 67). The duration of the retrospective portion of the study was 12-24 months. Due to slow enrollment, PROOF ended earlier than planned and the final duration of the prospective portion of the study was 6 months. Therefore, between 18 and 30 months of efficacy and tolerability data were available for analysis., Results: After controlling for baseline disability level, Expanded Disability Status Scale (EDSS) scores revealed no statistically significant differences between the treatment groups during the prospective portion of the study, with sustained disability progression similar in both groups (25.8% IM IFNbeta-1a 30 mug once weekly vs. 26.7% SC IFNbeta-1a 44 mug three times per week). Relapse rates were similar in the groups, as were MRI endpoints of brain parenchymal fraction, T1 lesion volume, T2 lesion volume, number of new/enlarging T2 lesions, and gadolinium-enhancing (Gd+) lesion volume and count. Treatment groups differed in frequency of NAbs, with 19% of patients treated with SC IFNbeta-1a 44 microg three times per week NAb+ compared with none treated with IM IFNbeta-1a 30 microg once weekly. More NAb+ patients compared with NAb- patients had disability progression (40.0% vs. 27.8%, p = NS), new or enlarging T2 lesions at the end of treatment (63.6% vs. 40.7%, p = 0.003), and Gd+ lesions after 12-24 months of treatment (36.4% vs. 15%, p = 0.001). The IFNbeta-1a products had comparable tolerability. However, fewer patients treated with IM IFNbeta-1a 30 microg once weekly had injection-site reactions (2.9% vs. 6.0%). Limitations of this study include its design and sample size, both of which hinder detection of differences in efficacy between IFNbeta-1a treatments., Conclusions: The results of the present study show that the two IFNbeta-1a products have comparable efficacy and differing immunogenicity.

Background: Despite its prominence in Canadian history, there are few publications about the Halifax Explosion of 1917 that deal with the care of victims with eye injuries., Methods: Archived documents relating to the nature and treatment of eye injuries sustained during the Halifax Explosion were reviewed at the Public Archives of Nova Scotia and the Maritime Museum of the Atlantic. A review of current literature was performed., Results: Detailed accounts regarding the personal and surgical experience of 2 ophthalmologists, G.H. Cox and F.T. Tooke, were found. Several unpublished government and personal documents on eye injuries sustained during the Halifax Explosion are filed at the Public Archives of Nova Scotia. Twelve ophthalmologists treated 592 people with eye injuries and performed 249 enucleations. Sixteen people had double enucleations. Most of the eye injuries were caused by shards of shattered glass. Sympathetic ophthalmia was the feared complication for penetrating eye injuries and a common indication for enucleation in 1917. A Blind Relief Fund was established to help treat, rehabilitate, and compensate the visually impaired., Interpretation: Many of the eye injuries sustained during the Halifax Explosion were due to flying shards of glass. Details of their treatment provide insight into a unique and devastating event in Canadian medical history and demonstrate how eye injuries were managed in 1917.

Background: Declining human reproductive health over the last 60 years has been proposed to be due to effects of environmental chemicals, especially endocrine disrupting compounds, on fetal development. We investigated whether a model pesticide, dieldrin, at concentrations within both maternal circulation and environmental ranges (1 pmol/l = 0.0004 p.p.b. = 380.9 pg/l), could disrupt the human fetal testis., Methods: Human fetal testes were collected during the second trimester, a critical period of male sexual differentiation (development and masculinization). Testis explants were cultured for 24 h in the presence and absence of LH (10-1000 IU LH/l) and dieldrin (1 pmol and 1 nmol/l). Endocrine, immunohistological and proteome characteristics of the tissues were investigated., Results: Exposure to dieldrin reduced LH-induced testosterone secretion (P < 0.05) and tissue protein concentrations of LH receptor and steroid acute regulatory protein (P < 0.05). Dieldrin altered proteins associated with cancer, apoptosis, transcription and development. Wnt-2b was reduced 3-fold and immunolocalized to Leydig and Sertoli cells. Dieldrin also reversed some LH-induced changes in protein expression, supporting the conclusion that Leydig cell function is at risk from environmental chemicals., Conclusions: Our findings indicate that exposure to very low, biologically relevant, concentrations of environmental chemicals could affect the fetal human Leydig cell, reducing testosterone secretion and potentially leading to subtle dysregulation of reproductive development and adult fecundity.

Objective: Our objective was to estimate the effectiveness of disease-modifying drugs (DMDs) in delaying multiple sclerosis (MS) disability progression in relapsing-onset (R-onset) definite MS patients under "real-world" conditions., Methods: Treatment effect size, for DMDs as a class, was estimated in absolute terms and relative to MS natural history. A basic model estimated annual Expanded Disability Status Scale (EDSS) change before and after treatment. An expanded model estimated annual EDSS change in pretreatment years, treatment years on first drug, treatment years after drugs were switched, and in years after treatment stopped. Models were populated with 1980 through 2004 clinical data, including 1988 through 2004 data for all Nova Scotians treated with DMDs. Estimates were made for relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and R-onset groups., Results: Estimated pretreatment annual EDSS increases were approximately 0.10 of one EDSS point for the RRMS group, 0.31 for the SPMS group, and 0.16 for the R-onset group. Estimates of EDSS increase avoided per treatment year on the first drug were significant for the RRMS group (-0.103, 0.000), the SPMS group (-0.065, 0.011), and the R-onset group (-0.162, 0.000); relative effect size estimates were 112%, 21%, and 105%. Estimated EDSS progression was faster in years after drug switches and treatment stops., Conclusions: Our estimates of disease-modifying drug (DMD) relative treatment effect size, in the context of "real-world" clinical practice, are similar to DMD treatment efficacy estimates in pivotal trials, though our findings attained statistical significance. DMDs, as a class, are effective in delaying Expanded Disability Status Scale progression in patients with relapsing-onset definite multiple sclerosis (MS) (90%), although effectiveness is much better for relapsing-remitting MS than for secondary progressive MS groups.

Explosions, man-made and accidental, continue to require improved emergency medical responses. In the 1917 Halifax Explosion, an inordinate number of penetrating eye injuries occurred. A review of their treatment provides insight into a traumatic event with unique ophthalmological importance. Archived personal and government documents relating to the Halifax Explosion were reviewed at the Public Archives of Nova Scotia, Canada, along with a review of current literature. Twelve ophthalmologists treated 592 people with eye injuries and performed 249 enucleations. Sixteen people had both eyes enucleated. Most of the eye injuries were caused by shards of shattered glass. A Blind Relief Fund was established to help treat and rehabilitate the visually impaired. The injured were given pensions through the Canadian National Institute for the Blind, Toronto, Ontario, Canada, which continue to this day. Sympathetic ophthalmia was the feared complication for penetrating eye injuries and a common indication for enucleation in 1917. Even so, the severity and the overwhelming number of eye injuries sustained during the Halifax Explosion made it impossible for lengthy eye-saving procedures to be performed. Enucleation was often the only option.

Exposure of the fetus to excess estrogen is believed to increase the risk of developing breast cancer during adult life. Fetal exposure to low doses of the xenoestrogen bisphenol A resulted in long-lasting effects in the mouse mammary gland that were manifested during adult life. It enhanced sensitivity to estradiol, decreased apoptosis, increased the number of progesterone receptor-positive epithelial cells at puberty and increased lateral branching at 4 months of age. We now report that fetal exposure to 2.5, 25, 250 and 1000 microg bisphenol A/kg body weight/day induces the development of ductal hyperplasias and carcinoma in situ at postnatal day 50 and 95 in rats. These highly proliferative lesions have an increased number of estrogen receptor-alpha positive cells. Thus, fetal bisphenol A exposure is sufficient to induce the development of preneoplastic and neoplastic lesions in the mammary gland in the absence of any additional treatment aimed at increasing tumor development.

Objective: Previous studies have suggested that the incidence of amyotrophic lateral sclerosis (ALS) in Nova Scotia is relatively high and increasing over time. This study was performed to determine the current incidence of ALS in Nova Scotia and to compare this to data collected in 1984 and 1995., Methods: All physiatrists and neurologists were surveyed on a monthly basis over one year to record all new cases of ALS diagnosed in Nova Scotia. Data was compared to that collected using similar methods in 1984 and 1995. To validate our methods, we also performed a retrospective study using a provincial health care database., Results: There were 21 new ALS cases in Nova Scotia during the 2003 study period, yielding a crude incidence of 2.24/100,000. The age-adjusted incident rate for 2003 was 2.13 (95% CI = 0.11-4.15). The age-adjusted rate for 1995 was 2.3 (95% CI = 0.08-4.53) while the age-adjusted rate for 1984 was 2.22 (95% CI = 0.13-4.32). Analysis of provincial health records identified 24 cases of ALS and an age-adjusted incidence of 2.44/100,000., Conclusions: The age-adjusted incidence of ALS in Nova Scotia has remained stable over the period 1984-2003. The incidence is similar to that reported in several other parts of the world.

Mitoxantrone, an immunosuppressant agent with potent anti-inflammatory activity, has been used to treat patients with multiple sclerosis (MS) who have worsening relapsing-remitting (RRMS) or secondary progressive multiple sclerosis (SPMS) despite prior therapy with interferons or glatiramer acetate. From previous experience of treating cancer with mitoxantrone, it was expected that cardiotoxic effects and occasional malignancy would develop in some patients treated with this agent. From the earliest trials, reduction of left ventricular ejection fraction (LVEF) was seen in 2-3% of cases, and in some this effect may persist and less commonly there can be congestive heart failure and even death. There are also occasional reports of leukaemia developing in MS patients treated with this agent. Mitoxantrone has been shown to reduce relapses, the number of new lesions visualised on magnetic resonance imaging and stop or reduce the progression of the disease in many patients treated. The drug has found a place in MS therapy because in this progressing group of MS patients who are failing on the disease-modifying therapies with interferons or glatiramer acetate, trials have shown that mitoxantrone may arrest or even improve many patients. Recognising the risks, mitoxantrone therapy is a reasonable option for MS patients with RRMS and SPMS who are progressing despite current disease-modifying therapy.

Introduction: This study was designed to determine if and how a non-toxic, naturally occurring bioflavonoid, galangin, affects proliferation of human mammary tumor cells. Our previous studies demonstrated that, in other cell types, galangin is a potent inhibitor of the aryl hydrocarbon receptor (AhR), an environmental carcinogen-responsive transcription factor implicated in mammary tumor initiation and growth control. Because some current breast cancer therapeutics are ineffective in estrogen receptor (ER) negative tumors and since the AhR may be involved in breast cancer proliferation, the effects of galangin on the proliferation of an ER-, AhRhigh line, Hs578T, were studied., Methods: AhR expression and function in the presence or absence of galangin, a second AhR inhibitor, alpha-naphthoflavone (alpha-NF), an AhR agonist, indole-3-carbinol, and a transfected AhR repressor-encoding plasmid (FhAhRR) were studied in Hs578T cells by western blotting for nuclear (for instance, constitutively activated) AhR and by transfection of an AhR-driven reporter construct, pGudLuc. The effects of these agents on cell proliferation were studied by 3H-thymidine incorporation and by flow cytometry. The effects on cyclins implicated in mammary tumorigenesis were evaluated by western blotting., Results: Hs578T cells were shown to express high levels of constitutively active AhR. Constitutive and environmental chemical-induced AhR activity was profoundly suppressed by galangin as was cell proliferation. However, the failure of alpha-NF or FhAhRR transfection to block proliferation indicated that galangin-mediated AhR inhibition was either insufficient or unrelated to its ability to significantly block cell proliferation at therapeutically relevant doses (IC50 = 11 microM). Galangin inhibited transition of cells from the G0/G1 to the S phases of cell growth, likely through the nearly total elimination of cyclin D3. Expression of cyclins A and E was also suppressed., Conclusion: Galangin is a strong inhibitor of Hs578T cell proliferation that likely mediates this effect through a relatively unique mechanism, suppression of cyclin D3, and not through the AhR. The results suggest that this non-toxic bioflavonoid may be useful as a chemotherapeutic, particularly in combination with agents that target other components of the tumor cell cycle and in situations where estrogen receptor-specific therapeutics are ineffective.