History of Innate Immunity in Neurodegenerative Disorders

The foundations of innate immunity in neurodegenerative disorders were first laid by Del Rio Hortega (1919). He identified and named microglia, recognizing them as cells of mesodermal origin. Van Furth in 1969 elaborated the monocyte phagocytic system with microglia as the brain representatives. Validation of these concepts did not occur until 1987 when HLA-DR was identified on activated microglia in a spectrum of neurological disorders. HLA-DR had already been established as a definitive marker of immunocompetent cells of mesodermal origin. It was soon determined that the observed inflammatory reaction was an innate immune response. A rapid expansion of the field took place as other markers of an innate immune response were found that were made by neurons, astrocytes, oligodendroglia, and endothelial cells. The molecules included complement proteins and their regulators, inflammatory cytokines, chemokines, acute phase reactants, prostaglandins, proteases, protease inhibitors, coagulation factors, fibrinolytic factors, anaphylatoxins, integrins, free radical generators, and other unidentified neurotoxins. The Nimmerjahn movies demonstrated that resting microglia were constantly active, sampling the surround, and responding rapidly to brain damage. Ways of reducing the neurotoxic innate immune response and stimulating a healing response continue to be sought as a means for ameliorating the pathology in a spectrum of chronic degenerative disorders

Testing the Underlying Chemical Principles of the Biotic Ligand Model (BLM) to Marine Copper Systems: Measuring Copper Speciation Using Fluorescence Quenching

Speciation of copper in marine systems strongly influences the ability of copper to cause toxicity. Natural organic matter (NOM) contains many binding sites which provides a protective effect on copper toxicity. The purpose of this study was to characterize copper binding with NOM using fluorescence quenching techniques. Fluorescence quenching of NOM with copper was performed on nine sea water samples. The resulting stability con- stants and binding capacities were consistent with literature values of marine NOM, show- ing strong binding with log K values from 7.64 to 10.2 and binding capacities ranging from 15 to 3110 nmole mg C −1 . Free copper concentrations estimated at total dissolved copper concentrations corresponding to previously published rotifer effect concentrations, in the same nine samples, were statistically the same as the range of free copper calculated for the effect concentration in NOM-free artificial seawater. These data confirms the applicability of fluorescence spectroscopy techniques for NOM and copper speciation characterization in sea water and demonstrates that such measured speciation is consistent with the chemical principles underlying the Biotic Ligand Model (BLM) approach for bioavailability-based metals risk assessment

Effects of Chronic Waterborne Nickle Exposure on Two Successive Generations of \u3cem\u3eDaphnia Magna\u3c/em\u3e

In a 21-d chronic toxicity test in which an F0 generation of Daphnia magna were exposed to waterborne Ni, the noobservable-effect concentration (for survival, reproduction, and growth) was 42 μg Ni L-1, or 58% of the measured 21-d median lethal concentration (LC50) of 71.9 μg Ni L-1 (95% confidence interval, 56.5–95.0). Chronic exposure to 85 μg Ni L-1 caused marked decreases in survival, reproduction, and growth in F0 animals. In the F1 generation (daphnids born of mothers from the chronically exposed F0 generation), animals chronically exposed to 42 μg Ni L-1 for 11 d weighed significantly less (20%) than controls, indicating increased sensitivity of F1 animals. Additionally, in this successive generation, significant decreases in whole-body levels of metabolites occurred following exposure to both 42 μg Ni L-1 (decreased glycogen and adenosine triphosphate [ATP]) and 21 μg Ni L-1 (decreased ATP). No significant changes were observed in whole-body total lipid, total protein, and lactate levels at any concentration. Whereas F1 neonates with mothers that were exposed to 21 μg Ni L-1 showed increased resistance to acute Ni challenge, as measured by a significant (83%) increase in the acute (48-h) LC50, F1 neonates with mothers that were exposed to 42 μg Ni L-1 were no more tolerant of acute Ni challenge than control animals were. Nickel accumulations in F1 animals chronically exposed to 21 and 42 μg Ni L-1 were 11- and 18-fold, respectively, above control counterparts. The data presented suggest that chronic Ni exposure to two successive generations of D. magna lowered the overall energy state in the second generation. Whereas the quantity of neonates produced was not affected, the quality was; thus, environmentally meaningful criteria for regulating waterborne Ni concentrations in freshwater require consideration of possible multigenerational effects

“Here come the Canadians … to restore our freedom to us”: “And we will praise God, when the Canadians … have vanished back to Canada”

The following editorials and articles, translated from the Nijmegen newspaper De Gelderlander, offer English-language readers insight into the concerns and perspectives of the Dutch as they dealt with the uneven transition from occupation to liberation and the welcome yet at times troublesome presence of the Allied forces, the Canadians in particular. Although the physical damage inflicted by the war was everywhere visible, it was the moral and psychological effect of the occupation on the young that formed the greatest source of concern, especially when those who had come of age during years of deprivation and disorientation encountered exotic young soldiers eager to enjoy the pleasures of life after years of training and combat. The articles reveal the conflicting reactions of the liberated to their liberators in an extraordinary and unprecedented set of circumstances

“We are now getting a Canadian occupation”: Liberators and the Liberated in the Nijmegen Salient, 1944-45

Liberation came at a high price to the already devastated city of Nijmegen during Operation Market Garden. It remained a frontline city for nearly seven months, during which time Nijmegen and the surrounding area came to be “occupied” by 1st Canadian Army. The presence of a friendly but foreign army was welcome but proved to be a mixed blessing as the local inhabitants sought to resume control of their lives in a time of shortages, suspension of normal morality and conflict between the Dutch themselves. The protracted stay of the Canadians after the war was frustrating for both the liberators and the liberated. The warm afterglow of Dutch gratitude to the Canadians rightly prevails today but should not lead us to see the liberation and its aftermath in solely heroic rather than in the very human terms reflected in diaries, newspapers and other sources from that unusual, chaotic time

Effects of Chronic Cd Exposure via the Diet or Water on Internal Organ-Specific Distribution and Subsequent Gill Cd Uptake Kinetics in Juvenile Rainbow Trout (\u3cem\u3eOncorhynchus mykiss\u3c/em\u3e)

New regulatory approaches to metal toxicity (e.g., biotic ligand model [BLM]) focus on gill metal binding and tissue specific accumulation of waterborne metals; the dietary route of exposure and dietary/waterborne interactions are not considered, nor are the consequences of chronic exposure by either route. Therefore, we studied the effect of the same gill Cd load (∼μ2.5 mg/g), achieved by a chronic, 30-d exposure to Cd either via the diet (1,500 mg/kg) or the water (2 μg/L), on tissue-specific Cd distribution and subsequent uptake of waterborne Cd in juvenile rainbow trout (Oncorhynchus mykiss). These two exposure regimes resulted in a branchial Cd load that had been taken up across either apical gill membranes (waterborne Cd) or basolateral gill membranes (through the bloodstream for dietary Cd). The BLM characteristics of the gills (i.e., short-term Cd uptake kinetics) were altered: affinity (log KCd-Gill [95% confidence level]) decreased from 7.05 (6.75–8.76) for control to 6.54 (6.32–7.03) for waterborne Cd and 5.92 (5.83–6.51) for dietary Cd, whereas binding capacity (Bmax) increased from 3.12 (2.14–4.09) to 4.80 (3.16–6.43) and 5.50 (2.86–8.17) nmol·g-1 for control, waterborne, and dietary Cd, respectively. Fish exposed to dietary Cd accumulated a much greater overall chronic Cd body burden relative to fish exposed to waterborne Cd or control fish. The carcass accumulated the greatest percentage of total body Cd in control and waterborne-exposed fish, whereas the intestinal tissue accumulated the greatest percentage in dietary-exposed fish. Tissue-specific Cd burdens were highest in the kidney in both dietary and waterborne treatments. We conclude that chronic Cd exposure alters Cd uptake dynamics, and that the route of Cd exposure, whether waterborne or dietary, results in differences of internal Cd accumulation and branchial Cd uptake characteristics. These factors should be considered in future BLM development

Protective Effects of Calcium Against Chronic Waterborne Cadmium Exposure to Juvenile Rainbow Trout

Juvenile rainbow trout (Oncorhynchus mykiss [Walbaum]) on 1% daily ration were exposed to 0 (control) or 2 μg of cadmium as Cd(NO3)2·4H2O per liter added to four different calcium (Ca) concentrations: 260 (background), 470 (low), 770 (medium), or 1200 (high) μM of Ca added as Cd(NO3)2·4H2O in synthetic soft water for 30 d. Mortality was highest (;80%) in the background 1 Cd treatment. Approximately 40% mortality was observed in the low 1 Cd exposure; mortality was 10% or less for all other treatments. No growth effects were seen for any of the exposures. Kidneys accumulated the greatest concentration of Cd during the 30 d, followed by gills and livers. Accumulation of Cd in gills, kidney, and liver decreased at higher water Ca concentrations. No differences in whole-body or plasma Ca concentrations were found. Swimming performance was impaired in the low + Cd-exposed fish. Influx of Ca2+ into whole bodies decreased as water Ca concentrations increased; influx of Ca2+ into background + Cd–treated fish was significantly reduced compared to that in control fish. Experiments that measured uptake of new Cd into gills showed that the affinity of gills for Cd (KCd-gill) and the number of binding sites for Cd decreased as water Ca concentrations increased. Acute accumulation of new Cd into gills and number of gill Cd-binding sites increased with chronic Cd exposure, whereas the affinity of gills for Cd decreased with chronic Cd exposure. Longer-term gill binding (72 h) showed reduced uptake of new Cd at higher water Ca levels and increased uptake with chronic Cd exposure. Complications were found in applying the biotic ligand model to fish that were chronically exposed to Cd because of discrepancies in the maximum number of gill Cd-binding sites among different studies

Physiological Effects of Chronic Copper Exposure to Rainbow Trout (\u3cem\u3eOncorhynchus Mykiss\u3c/em\u3e) in Hard and Soft Water: Evaluation of Chronic Indicators

Effects of chronic copper exposure on a suite of indicators were examined: acute toxicity, acclimation, growth, sprint performance, whole-body electrolytes, tissue residues, and gill copper binding characteristics. Juvenile rainbow trout were exposed for 30 d to waterborne copper in hard water (hardness = 120 μg/L as CaCO3, pH = 8.0, Cu = 20 and 60 μg/L) and soft water (hardness = 20 μg/L as CaCO3, pH = 7.2, Cu = 1 and 2 μg/L). Significant acclimation to the metal occurred only in fish exposed to 60 mg/L, as seen by an approx. twofold increase in 96-h LC50 (153 vs 91 μg Cu/L). Chronic copper exposure had little or no effect on survival, growth, or swimming performance in either water hardness, nor was there any initial whole-body electrolyte loss (Na+ and Cl-). The present data suggest that the availability of food (3% wet body weight/day, distributed as three 1% meals) prevented growth inhibition and initial ion losses that usually result from Cu exposure. Elevated metal burdens in the gills and livers of exposed fish were measures of chronic copper exposure but not of effect. Initial gill binding experiments revealed the necessity of using radiolabeled Cu (64Cu) to detect newly accumulated Cu against gill background levels. Using this method, we verified the presence of saturable Cu-binding sites in the gills of juvenile rainbow trout and were able to make estimates of copperbinding affinity (log Kgill=Cu) and capacity (Bmax). Furthermore, we showed that both chronic exposure to Cu and to low water calcium had important effects on the Cu-binding characteristics of the gills