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Treatment modalities for breast cancer, including cyclophosphamide chemotherapy, have been associated with the development of cognitive decline (CRCD), which is characterized by impairments in memory, concentration, attention, and executive functions. We and others have identified a link between inflammation and decreased cognitive performance in patients with breast cancer receiving chemotherapy. In order to better understand the inflammation-associated molecular changes within the brain related to tumor alone or in combination with chemotherapy, we orthotopically implanted mouse mammary tumors (E0771) into female C57BL/6 mice and administered clinically relevant doses of cyclophosphamide and doxorubicin intravenously at weekly intervals for four weeks. We measured serum cytokines and markers of neuroinflammation at 48 h and up to one month post-treatment and tested memory using a reward-based delayed spatial alternation paradigm. We found that breast tumors and chemotherapy altered systemic inflammation and neuroinflammation. We further found that the presence of tumor and chemotherapy led to a decline in memory over time at the longest delay, when memory was the most taxed, compared to shorter delay times. These findings in a clinically relevant mouse model shed light on possible biomarkers for CRCD and add to the growing evidence that anti-inflammatory strategies have the potential to mitigate cancer- or treatment-related side effects.

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Artificial structures are an increasingly common feature of coastal marine environments. These structures are poor surrogates of natural rocky shores, and generally support less diverse communities and reduced population sizes. Little is known about sub-lethal effects of such structures in terms of demographic properties and reproductive potential, both of which may influence the dynamics and long-term viability of populations. This study examines the population structure, reproductive states and embryo production of Nucella lapillus populations on artificial structures and natural shores in Ireland and Wales. Population density was measured twice at six natural shores and six artificial structures: once in winter and once in spring. At each sampling, the shell height of 100 individuals from each site was measured. Monthly collections of adult specimens and egg capsules were made at each site from November-January and from March-May, in order to determine sex ratios, reproductive states, and embryo abundances. Artificial structures supported larger individuals and very few juveniles compared to natural shores. Between December and January, natural shores experienced a distinctive pulse in spawning activity followed by a decline in the proportion of females in a reproductive state, whereas on artificial structures the proportion of reproductive females remained relatively stable. Differences observed may be due to a lack of microhabitats on artificial structures, along with subtle variations in structure slope. Eco-engineering interventions, including the addition of refugia such as cracks and crevices, may allow N. lapillus populations on artificial structures to approximate those on natural shores.

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Artificial structures often support depauperate communities compared to natural rocky shores. Understanding variation in ecological success across shore types, particularly regarding habitat-forming species or those with structuring roles, is important to determine how artificial structure proliferation may influence ecosystem functioning and services. We investigated the population structure, sex ratio and reproductive potential of limpets on natural shores and artificial structures on Irish Sea coasts. Limpets were generally less abundant and Patella vulgata populations were often male dominated on artificial structures compared to natural shores, suggesting that shore type may influence these factors. P. vulgata length varied across sites within the Irish Sea (nested in coast and shore type) in autumn/winter, as well as temporally across sites along the Welsh coast. There was no difference in the proportion of P. vulgata in advanced stages of gonad development across shore types. The results suggest that rip-rap artificial structures may provide a habitat comparable to natural shores, however, the addition of ecological engineering interventions on artificial structures may allow limpet populations to better approximate those on natural shores.

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BACKGROUND: Inflammation may contribute to cognitive difficulties in patients with breast cancer. We tested 2 hypotheses: inflammation is elevated in patients with breast cancer vs noncancer control participants and inflammation in patients is associated with worse attention and processing speed over the course of chemotherapy. METHODS: Serum cytokines (interleukin [IL]-4, 6, 8, 10; tumor necrosis factor [TNF]-α) and soluble receptors [sTNFRI, II]) were measured in 519 females with breast cancer before and after chemotherapy and 338 females without cancer serving as control participants. Attention and processing speed were measured by Rapid Visual Processing (RVP), Backward Counting (BCT), and Trail Making-A (TMT-A) tests. Linear regression models examined patient vs control cytokines and receptor levels, adjusting for covariates. Linear regression models also examined relationships between patient cytokines and receptor levels and test performance, adjusting for age, body mass index, anxiety, depression, cognitive reserve, and chemotherapy duration. Statistical tests were 2-sided (α = .05). RESULTS: sTNFRI and sTNFRII increased over time in patients relative to controls, whereas IL-4, IL-6, and IL-10 decreased. Prechemotherapy, higher IL-8 associated with worse BCT (ß = 0.610, SE = 0.241, P = .01); higher IL-4 (ß = -1.098, SE = 0.516, P = .03) and IL-10 (ß = -0.835, SE = 0.414, P = .04) associated with better TMT-A. Postchemotherapy, higher IL-8 (ß = 0.841, SE = 0.260, P = .001), sTNFRI (ß = 6.638, SE = 2.208, P = .003), and sTNFRII (ß = 0.913, SE = 0.455, P = .045) associated with worse BCT; higher sTNFRII also associated with worse RVP (ß = -1.316, SE = 0.587, P = .03). At prechemotherapy, higher IL-4 predicted RVP improvement over time (ß = 0.820, SE = 0.336, P = .02); higher sTNFRI predicted worse BCT over time (ß = 5.566, SE = 2.367, P = .02). Longitudinally, increases in IL-4 associated with BCT improvement (ß = -0.564, SE = 0.253, P = .03). CONCLUSIONS: Generally, worse attention and processing speed were associated with higher inflammatory cytokines and receptors and lower anti-inflammatory cytokines in patients; future confirmatory studies are needed.

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Cancer-related cognitive decline (CRCD) is a clinically important problem and negatively affects daily functioning and quality of life. We conducted a pilot longitudinal study from pre- to post-chemotherapy in patients with breast cancer to assess changes in inflammation and cognition over time, as well as the impact of baseline cytokine level on post-chemotherapy cognitive scores. We found that concentrations of IL-6, MCP-1, sTNFRI, and sTNFRII significantly increased in patients, while IL-1ß significantly decreased (p < 0.05). After controlling for covariates, increases in IL-6 and MCP-1 were associated with worse executive function and verbal fluency in patients from pre- to post-chemotherapy (p < 0.05). Higher baseline IL-6 was associated with better performance on executive function and verbal fluency post chemotherapy (p < 0.05). Overall, these results suggest that chemotherapy-associated increases in cytokines/receptors is associated with worse cognitive function. Larger studies are needed to confirm these findings.

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Artificial structures are widespread features of coastal marine environments. These structures, however, are poor surrogates of natural rocky shores, meaning they generally support depauperate assemblages with reduced population sizes. Little is known about sub-lethal effects of such structures, for example, in terms of demographic properties and reproductive potential that may affect the dynamics and long-term viability of populations. Such understanding is particularly important for ecosystem engineer species, such as the intertidal seaweed Fucus vesiculosus. In this study, F. vesiculosus was sampled on eight artificial structures and eight natural shores along the east coast of Ireland and the west coast of Wales. Algal percentage cover, biomass, density of individuals, and growth rate did not differ between artificial and natural shores. Growth and reproductive cycles were consistent with previous studies for this species. While there was considerable variation from site to site, on average, populations on natural shores produced a higher number of mature receptacles during the peak reproductive period in April, and lower rates of dislodgement than on artificial structures. As F. vesiculosus reach peak reproductive output after 24 months, this suggests that individuals may be removed from populations on artificial structures before reaching their full reproductive potential. In this case, this did not influence density, percentage cover, or biomass, which suggests that F. vesiculosus populations on artificial structures may function similarly to those on natural shores if supported by suitable source populations, but potentially may not persist otherwise.

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The objective of this study was to evaluate the effect of plantain (Plantago lanceolata L.) on water dynamics and balance, as well as nitrogen (N) excretion by red deer (Cervus elaphus L.) as a potential forage tool to reduce negative environmental impacts. This experiment used a crossover design with red deer (n = 8) in metabolism crates to determine how fresh-cut herbage diets of either plantain or ryegrass (Lolium perenne L.) compared in terms of dry matter intake (DMI), diet digestibility, water dynamics, and N dynamics. Deer consuming plantain had greater water intake from herbage (P < 0.01) compared with ryegrass. Additionally, when fed plantain, deer had greater water excretion from urine (P < 0.01; 69.4%) and feces (P < 0.01; 29.4%) and, thus, total water excretion (P < 0.01; 61.7%) than when fed ryegrass. When consuming plantain, deer had greater DMI (P = 0.02; +11.2%) and fecal output (P < 0.01; +36.8%) and lower apparent dry matter digestibility (P = 0.03; -8.3%) compared with ryegrass. Plantain (15.9%) contained 30% less crude protein than ryegrass (22.8%) so that even with the greater DMI of plantain, plantain had lower (P < 0.01; -23%) N intake (g/d). Deer consuming plantain had lower urine N concentration (P < 0.01) than when consuming ryegrass. Additionally, deer consuming plantain had much less daily urine N (P < 0.01; -34.9%) excretions. Our results indicate deer fed plantain had greater DMI, ingested more water, and excreted more water than those consuming ryegrass, with lower urinary N (UN) concentration and lesser daily urine N excretion. Thus, we conclude that offering red deer plantain may reduce the environmental impact associated with UN output, such as nitrate leaching or N2O emissions to the atmosphere.

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The objective of this experiment was to determine appropriate methods for estimating fecal output, digestibility, and intake in red deer (Cervus elaphus). Dry matter intake (DMI), digestibility, and fecal output were estimated using the dual-marker (titanium dioxide; TiO2 and indigestible acid detergent fiber) technique, double n-alkane ratio technique (ALK) and the pulse dose (Yttrium; Y) technique to determine a suitable method to estimate DMI, fecal output, and digestibility measurements. Four male and four female deer were stratified by sex and randomly assigned either fresh-cut perennial ryegrass (Lolium perenne L.) or fresh-cut plantain (Plantago lanceolata) ad libitum in a cross-over design experiment. Actual DMI (mean ± SD: 1.5 ± 0.36 kg DM/d), digestibility (0.70 ± 0.06), and fecal output (0.45 ± 0.1 kg DM/d) were measured daily over the collection periods, and the average of each period was used for methods' comparison. The ALK method adequately estimated digestibility and fecal output of plantain; however, overestimated digestibility (P < 0.05) and DMI of ryegrass, so that there was no statistical agreement (P > 0.10) in DMI when diets were pooled. The overestimated DMI of the ryegrass diet led to ALK predicting greater intake when deer consumed ryegrass than plantain, which was the opposite of actual measurements. The pulse dosed Y overestimated (P < 0.05) fecal output and consequently DMI for both plantain and ryegrass, however, indicated similar trends to actual values. The dual-marker technique using TiO2 was able to detect the statistical differences between plantain and ryegrass as the actual measurements, had moderate to strong precision (r = 0.50 to 0.66) and statistical agreement (P < 0.05) with the pooled diet data. Therefore, the dual-marker technique provided the best alternative estimation method to actual measurements of forage DMI of grazing red deer.

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BACKGROUND: Cancer-related cognitive impairment (CRCI) is often related to chemotherapy. Increased chronic inflammation is believed to play a key role in the development of CRCI related to chemotherapy but studies assessing this hypothesis specifically in patients receiving chemotherapy are rare. METHODS: We assessed several cognitive domains using the Cambridge Neuropsychological Test Automated Battery (CANTAB) in twenty-two breast cancer patients currently receiving chemotherapy. We also measured inflammatory cytokine and receptor (MCP-1, TNF-α, sTNFRI, sTNFRII) concentrations in patient sera using Luminex assays. These concentrations were log-transformed to obtain a normal distribution. Associations between log-transformed cytokines and cognition were evaluated using Pearson correlations and linear regression, taking into account relevant covariates. RESULTS: Increased concentrations of sTNFRI and sTNFRII were associated with poorer performance on the CANTAB Delayed Matching to Sample (DMS, tests visual memory). Increasing sTNFRI levels were negatively correlated with DMS percent correct (r=-0.47, p=0.029) and DMS percent correct after a 12 second (s) delay (r=-0.65, p=0.001). Increasing levels of sTNFRII negatively correlated with DMS percent correct after 12s delay (r=-0.57, p=0.006). After controlling for relevant demographic (i.e. age, education) and clinical variables (i.e. disease stage, regimen type), we found that increased sTNFRI remained significantly related to decline on the DMS at the 12s delay (p=0.018). CONCLUSION: This preliminary study shows a significant association between higher sTNFRI and lower scores on the short-term visual memory delayed match to sample test in breast cancer patients receiving chemotherapy, supporting the hypothesis that sTNFRI is involved in CRCI.

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BACKGROUND: Cyclophosphamide chemotherapy is a mainstay of adjuvant breast cancer treatment. Unfortunately, this drug is associated with cognitive impairments in cancer patients that may accelerate cognitive aging. Memory is particularly affected in many patients. In order to better understand the precise cognitive impairments caused by this chemotherapy agent, we investigated a clinically relevant dose and administration paradigm on delayed spatial memory abilities in C57BL/6 mice. We utilized a delayed alternation paradigm similar to a delayed match to sample paradigm reported to be sensitive in human neurotoxicology research. METHODS: A dose of 200mg/kg cyclophosphamide was administered intravenously (at weekly intervals) for 4 weeks to C57BL/6 mice starting at 6 ½ months of age. Memory was tested in mice using a reward-based delayed spatial alternation paradigm with delay values of 1.5, 3, 6.1, 12.4 and 25s presented randomly over 80 sessions (16 reinforcers per session), and testing began at the initiation of chemotherapy through 3 months. RESULTS: At the longest delay, i.e., that requiring the greatest memory, mice treated with chemotherapy exhibited a significant decline over time in percent correct which leveled off compared to controls that continued to improve slightly. CONCLUSIONS: Our clinically relevant model shows cyclophosphamide chemotherapy causes a slight decline in delayed spatial memories at the longest delay that is sustained over time as mice age.

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The aryl hydrocarbon receptor (AhR) is a ligand-activated member of the basic-helix-loop-helix/PER-ARNT-SIM(PAS) transcription factor superfamily that also mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increasing evidence suggests that AhR influences the development of many tissues, including the central nervous system. Our previous studies suggest that sustained AhR activation by TCDD and/or AhR deletion disrupts cerebellar granule neuron precursor (GNP) development. In the current study, to determine whether endogenous AhR controls GNP development in a cell-autonomous manner, we created a GNP-specific AhR deletion mouse, AhR(fx/fx) /Math1(CRE/+) (AhR CKO). Selective AhR deletion in GNPs produced abnormalities in proliferation and differentiation. Specifically, fewer GNPs were engaged in S-phase, as demonstrated by ∼25% reductions in thymidine (in vitro) and Bromodeoxyuridine (in vivo) incorporation. Furthermore, total granule neuron numbers in the internal granule layer at PND21 and PND60 were diminished in AhR conditional knockout (CKO) mice compared with controls. Conversely, differentiation was enhanced, including ∼40% increase in neurite outgrowth and 50% increase in GABARα6 receptor expression in deletion mutants. Our results suggest that AhR activity plays a role in regulating granule neuron number and differentiation, possibly by coordinating this GNP developmental transition. These studies provide novel insights for understanding the normal roles of AhR signaling during cerebellar granule cell neurogenesis and may have important implications for the effects of environmental factors in cerebellar dysgenesis.

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Chemotherapeutic agents produce persistent difficulties in memory through an unknown mechanism. We tested the hypothesis that chemotherapeutic agents readily able to cross the blood-brain barrier (cyclophosphamide and fluorouracil), as opposed to those not known to readily cross the barrier (paclitaxel and doxorubicin), reduce neural cell proliferation following chemotherapy. We found that 5-bromo-2-deoxyuridine labeling following chemotherapy given to C57BL/6 mice revealed a similar reduction in neural cell proliferation in the dentate gyrus for all four agents. Insulin-like growth factor 1, a molecule implicated in promoting neurogenesis, counteracted the effects of high doses of chemotherapy on neural cell proliferation.

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An iterative learning algorithm for performing Multi-Channel Coherence Analysis (MCCA) is developed in this paper. MCCA is an extension of the well-known Canonical Correlation Analysis (CCA) that allows for more than two data channels to be analyzed. This paper discusses a standard method for performing MCCA and compares it to a newly developed data-driven and iterative approach. The proposed algorithm is then tested on two examples and its performance is evaluated in terms of estimation errors with respect to the values obtained using the standard MCCA algorithm. The first example uses a synthesized data set while the second example uses a real data set based on multi-spectral satellite imagery of the Earth's surface.

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The widespread environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been linked to developmental neurotoxicity associated with abnormal cerebellar maturation in both humans and rodents. TCDD mediates toxicity via binding to the aryl hydrocarbon receptor (AhR), a transcription factor that regulates the expression of xenobiotic metabolizing enzymes and growth regulatory molecules. Our previous studies demonstrated that cerebellar granule neuron precursor cells (GNPs) express transcriptionally active AhR during critical developmental periods. TCDD exposure also impaired GNP proliferation and survival in vitro. Therefore, this study tested the hypothesis that TCDD exposure disrupts cerebellar development by interfering with GNP differentiation. In vivo experiments indicated that TCDD exposure on postnatal day (PND) 6 resulted in increased expression of a mitotic marker and increased thickness of the external granule layer (EGL) on PND10. Expression of the early differentiation marker TAG-1 was also more pronounced in postmitotic, premigratory granule neurons of the EGL, and increased apoptosis of GNPs was observed. On PND21, expression of the late GNP differentiation marker GABA(A alpha 6) receptor (GABAR(A alpha 6)) and total estimated cell numbers were both reduced following exposure on PND6. Studies in unexposed adult AhR(-/-) mice revealed lower GABAR(A alpha 6) levels and DNA content. In vitro studies showed elevated expression of the early differentiation marker p27/Kip1 and the GABAR(A alpha 6) in GNPs following TCDD exposure, and the expression patterns of proteins related to granule cell neurite outgrowth, beta III-tubulin and polysialic acid neural cell adhesion molecule, were consistent with enhanced neuroblast differentiation. Together, our data suggest that TCDD disrupts a normal physiological role of AhR, resulting in compromised GNP maturation and neuroblast survival, which impacts final cell number in the cerebellum.

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BACKGROUND: The aim of this study was a detailed endoscopic-pathologic assessment of patients with various forms of GI strongyloidiasis. METHODS: Six patients with a diagnosis of GI strongyloidiasis who underwent endoscopic evaluation during a 3-year period (January 1998-January 2001) were included. Published information was reviewed in detail, focusing on the endoscopic features and the diagnostic approach to this parasitosis. OBSERVATIONS: Strongyloidiasis has a broad range of endoscopic features. In the duodenum, the findings included edema, brown discoloration of the mucosa, erythematous spots, subepithelial hemorrhages, and megaduodenum. In the colon, the findings included loss of vascular pattern, edema, aphthous ulcers, erosions, serpiginous ulcerations, and xanthoma-like lesions, and, in the stomach, thickened folds and mucosal erosions. A histopathologic diagnosis of strongyloidiasis was made in all cases. CONCLUSIONS: Strongyloidiasis can involve any segment of the GI tract. EGD with procurement of biopsy specimens from the duodenum was the most accurate method of diagnosis in this case series.

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PURPOSE: Genetic alterations that are associated with acute and chronic pancreatitis remain to be identified. METHODS: The authors investigated two functionally active tumor necrosis factor (TNF) promoter region polymorphisms at positions -238 and -308 and the entire coding region of the corresponding TNF receptor 1 (TNFR1) gene in 54 patients with hereditary, familial, and idiopathic chronic pancreatitis who were previously tested negative for cationic trypsinogen mutations by direct DNA sequencing. RESULTS: In three patients, we detected novel DNA variants in the TNFR1 gene that did not segregate with the disease. The genotype frequencies of the TNF promoter polymorphisms were similar between patients and controls. CONCLUSION: These polymorphisms are not associated with hereditary, familial, or idiopathic chronic pancreatitis.

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INTRODUCTION: Chronic alcohol consumption predisposes susceptible individuals to both acute and chronic pancreatitis. AIMS: Our hypothesis was that alcohol increases the risk of pancreatitis by disrupting defense mechanisms and/or enhancing injury-associated pathways through altered gene expression. Hence, we studied the expression of pancreatic genes in rats chronically exposed to ethanol. METHODOLOGY: Male Wistar rats were pair-fed liquid diets without and with ethanol for 4 weeks. Total RNA was extracted from rat pancreas and other organs. The mRNA expression patterns among pancreatic samples from ethanol-fed rats and controls were compared with use of mRNA differential display. The differentially expressed cDNA tags were isolated, cloned, and sequenced. RESULTS: One cDNA tag that was overexpressed in the pancreas showed 99% sequence homology to a rat pancreatic cholesterol esterase mRNA (CEL; Enzyme Commission number [EC] 3.1.1.13). The differential expression was confirmed by realtime PCR. Gene expression was also increased in the liver but not in the heart or brain of the alcohol-fed rats. Because CEL has fatty acid ethyl ester (FAEE)-generating activity and FAEEs play a major role in acute alcoholic pancreatitis, we determined the expression of other genes encoding for FAEE-generating enzymes and showed similar organ-specific expression patterns. CONCLUSION: Our results demonstrate that chronic ethanol consumption induced expression of FAEE-related genes in the pancreas and liver. This upregulation may be a central mechanism leading to acinar cell injury.

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