Breast cancer and cytomegalovirus.

PURPOSE: To determine whether cytomegalovirus is causally associated with breast cancer and whether cytomegalovirus should be categorised as an oncogenic virus. METHODS: We undertook a review of published epidemiological and laboratory studies, using established causal criteria: Bradford Hill criteria to determine whether cytomegalovirus is associated with breast cancer; and Evans/Mueller criteria to determine whether cytomegalovirus should be categorised as an oncogenic virus. RESULTS: Although there are inconsistencies in the findings of published epidemiological and laboratory studies, these may be explained by factors such as: differences in timing of blood samples, differences in selection of cases and controls, or high cytomegalovirus seroprevalence among participants in the epidemiological studies; and, in the laboratory studies, differences in sample preparations, age of sample, whether or not paired breast cancer and normal breast tissue samples were used, differences in the tests, primers and/or antibodies used, differences in histological types of breast cancer studied, and/or features of the virus. CONCLUSIONS: Overall, the results of published studies of cytomegalovirus and breast cancer suggest cytomegalovirus is a causal factor for at least some types of breast cancer. If the evidence for a link between cytomegalovirus and breast cancer continues to strengthen, further research could lead to: targeted screening; therapy using antiviral drugs; and, perhaps, primary prevention of a significant proportion of breast cancer. Vaccination against viruses has already been shown to be effective in preventing cervix and liver cancer; cytomegalovirus vaccines are already under development.

Which patients are satisfied with their overall outcome but dissatisfied with their return to recreational activities after total knee arthroplasty?

BACKGROUND: The primary aim of this study was to assess whether patients dissatisfied with both recreational activities and overall outcome were different to those dissatisfied with recreational activities but satisfied with their overall outcome one year after total knee arthroplasty (TKA). METHODS: A retrospective cohort consisting of 3324 primary TKA were identified from an established arthroplasty database. Patient demographics, comorbidities, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Short Form (SF) 12 scores were collected pre-operatively and one year post-operatively. Overall patient satisfaction and satisfaction with recreational activities were assessed at one year. RESULTS: The rate of patient satisfaction with recreational activities (n = 2672, 80.4%) was significantly (odds ratio (OR) 0.47, 95% confidence intervals (CI) 0.41 to 0.54, p < 0.001) lower than satisfaction with the overall outcome (n = 2982, 89.7%). When adjusting for confounding variables older age (OR 1.03, p = 0.008), increasing BMI (OR 1.05, p = 0.01) and absence of hypertension (OR 0.66, p = 0.02) were independent predictors of being dissatisfied with recreational activities in isolation. The one-year components and total WOMAC scores were significant (p < 0.001) predictors of satisfaction with recreational activities and were reliable with an area under the curve of ≥0.82 CONCLUSION: Patients of older age, higher BMI and without hypertension are more likely to be dissatisfied with recreational activities despite being satisfied with their overall outcome.

Patient age of less than 55 years is not an independent predictor of functional improvement or satisfaction after total knee arthroplasty.

INTRODUCTION: Management of the young patient with end-stage osteoarthritis of the knee is difficult, with surgical options of osteotomy, partial or total knee arthroplasty (TKA). The primary aim of this study was to assess whether age of less than 55 years was an independent predictor of functional outcome and satisfaction after total knee arthroplasty (TKA). The secondary aims were to identify pre-operative differences in patient demographics, comorbidity and function between patients less than 55 years old compared to those 55 years old and over. MATERIALS AND METHODS: A retrospective cohort consisting of 2589 patients undergoing a primary TKA was identified from an established arthroplasty database. Patient demographics, comorbidity, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Short Form (SF) 12 scores were collected pre-operatively and 1 year post-operatively. In addition, patient satisfaction was assessed at 1 year. Regression analysis was used to identify independent pre-operative predictors of change in the WOMAC and SF-12 scores, and patient satisfaction. RESULTS: Patients less than 55 years old were significantly less likely to be satisfied with the overall outcome of their TKA (OR 0.4, p = 0.001). After adjusting for confounding variables age group was not an independent predictor of overall satisfaction with overall outcome (OR 0.71, p = 0.16). Independent predictors of an increased risk of dissatisfaction with the overall outcome at 1 year were depression (OR 0.58, p = 0.008) and worse pre-operative SF-12 MCS (p = 0.04). CONCLUSION: Age of less than 55 years is not an independent predictor of functional outcome or rate of patient satisfaction after TKA. However, depression and poor mental health are significantly more prevalent in patients less than 55 years old and were independently associated with a lower satisfaction rate.

Translating colorectal cancer genetics into clinically useful biomarkers.

Colorectal cancer (CRC) is a major health problem worldwide accounting for over a million deaths annually. While many patients with Stage II and III CRC can be cured with combinations of surgery, radiotherapy and chemotherapy, this is morbid costly treatment and a significant proportion will suffer recurrence and eventually die of CRC. Increased understanding of the molecular pathogenesis of CRC has the potential to identify high risk patients and target therapy more appropriately. Despite increased understanding of the molecular events underlying CRC development, established molecular techniques have only produced a limited number of biomarkers suitable for use in routine clinical practice to predict risk, prognosis and response to treatment. Recent rapid technological developments, however, have made genomic sequencing of CRC more economical and efficient, creating potential for the discovery of genetic biomarkers that have greater diagnostic, prognostic and therapeutic capabilities for the management of CRC. This paper reviews the current understanding of the molecular pathogenesis of CRC, and summarizes molecular biomarkers that surgeons will encounter in current clinical use as well as those under development in clinical and preclinical trials. New molecular technologies are reviewed together with their potential impact on the understanding of the molecular pathogenesis of CRC and their potential clinical utility in classification, diagnosis, prognosis and targeting of therapy.

16. The fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010.

This chapter summarises the results of the preceding sections, which estimate the fraction of cancers occurring in the UK in 2010 that can be attributed to sub-optimal, past exposures of 14 lifestyle and environmental risk factors. For each of 18 cancer types, we present the percentage of cases attributable to one or all of the risk factors considered (tobacco, alcohol, four elements of diet (consumption of meat, fruit and vegetables, fibre, and salt), overweight, lack of physical exercise, occupation, infections, radiation (ionising and solar), use of hormones, and reproductive history (breast feeding)).Exposure to less than optimum levels of the 14 factors was responsible for 42.7% of cancers in the UK in 2010 (45.3% in men, 40.1% in women)--a total of about 134,000 cases.Tobacco smoking is by far the most important risk factor for cancer in the UK, responsible for 60, 000 cases (19.4% of all new cancer cases) in 2010. The relative importance of other exposures differs by sex. In men, deficient intake of fruits and vegetables (6.1%), occupational exposures (4.9%) and alcohol consumption (4.6%) are next in importance, while in women, it is overweight and obesity (because of the effect on breast cancer)--responsible for 6.9% of cancers, followed by infectious agents (3.7%).Population-attributable fractions provide a valuable quantitative appraisal of the impact of different factors in cancer causation, and are thus helpful in prioritising cancer control strategies. However, quantifying the likely impact of preventive interventions requires rather complex scenario modelling, including specification of realistically achievable population distributions of risk factors, and the timescale of change, as well as the latent periods between exposure and outcome, and the rate of change following modification in exposure level.

The long-term outcome of hip replacement in adults with juvenile idiopathic arthritis: the influence of steroids and methotrexate.

Juvenile idiopathic arthritis (JIA) is a chronic disease of childhood; it causes joint damage which may require surgical intervention, often in the young adult. The aim of this study was to describe the long-term outcome and survival of hip replacement in a group of adult patients with JIA and to determine predictors of survival for the prosthesis. In this retrospective comparative study patients were identified from the database of a regional specialist adult JIA clinic. This documented a series of 47 hip replacements performed in 25 adult patients with JIA. Surgery was performed at a mean age of 27 years (11 to 47), with a mean follow-up of 19 years (2 to 36). The mean Western Ontario and McMaster Universities osteoarthritis index questionnaire (WOMAC) score at the last follow-up was 53 (19 to 96) and the mean Health Assessment Questionnaire score was 2.25 (0 to 3). The mean pain component of the WOMAC score (60 (20 to 100)) was significantly higher than the mean functional component score (46 (0 to 97)) (p = 0.02). Kaplan-Meier survival analysis revealed a survival probability of 46.6% (95% confidence interval 37.5 to 55.7) at 19 years, with a trend towards enhanced survival with the use of a cemented acetabular component and a cementless femoral component. This was not, however, statistically significant (acetabular component, p = 0.76, femoral component, p = 0.45). Cox's proportional hazards regression analysis showed an implant survival rate of 54.9% at 19 years at the mean of covariates. Survival of the prosthesis was significantly poorer (p = 0.001) in patients who had been taking long-term corticosteroids and significantly better (p = 0.02) in patients on methotrexate.

Diversity of Abeta deposits in the aged brain: a window on molecular heterogeneity?

The Abeta peptide forms a morphologically heterogeneous assortment of aggregates in the brains of patients with Alzheimer's disease. The reasons for the diversity of the histopathologically identified lesions (Abeta-plaques and cerebral beta-amyloid angiopathy) are uncertain. However, there is growing evidence for the existence of higher order structural heterogeneity in protein molecules with the same amino acid sequence and differential involvement in disease. Focused analysis of plaque morphotypes could yield novel insights into the organization and function of putative protein variants in the diseased brain. In addition to classical amyloid-selective dyes, new techniques are emerging to undertake such analyses, including selective, small molecule binding agents, specific antibodies, and conformationally sensitive optical probes. By illuminating the relationships between specific lesions and their molecular components, these agents can help to clarify the complex pathology of Alzheimer's disease.

Depletion of ovarian follicles with age in chimpanzees: similarities to humans.

We retrieved ovarian sections taken from necropsies of 19 captive chimpanzees (Pan troglodytes) aged 0-47 yr, counted the number of primordial follicles in each, and compared the rate of decline in numbers to declines previously documented in humans. The follicular depletion rate in this sample was indistinguishable from that shown across the same ages in classic human data sets. This result supports earlier suggestions that ovarian senescence occurs at the same ages in chimpanzees and humans, implying that the influence of declining ovarian function on other physiologic systems may be distinctively buffered in humans.

Cerebral beta-amyloid angiopathy in aged squirrel monkeys.

Cerebral beta-amyloid angiopathy (CAA) is an age-related disorder of the brain vasculature that is involved in up to 20% of non-traumatic cerebral hemorrhage in humans. CAA is a risk factor for cognitive decline, and may exacerbate the dementia of Alzheimer's disease. Progress in discovering the cause and potential therapies for this disorder has been hindered by the paucity of animal models, particularly models of idiopathic CAA. The squirrel monkey (Saimiri spp) develops significant CAA in the natural course of aging. To evaluate the suitability of Saimiri as a model of human CAA, we studied the distribution and composition of Abeta subtypes in CAA and parenchymal (senile plaque) deposits in the brains of aged squirrel monkeys, as well as the relationship between vascular beta-amyloid deposition and comorbid vasculopathies that occur in aged humans. Our findings show that: 1) CAA consists ultrastructurally of classical amyloid fibrils and is the principal type of cerebral beta-amyloidosis in squirrel monkeys; 2) The two primary isoforms of Abeta (Abeta40 and Abeta42) coexist in most microvascular and parenchymal lesions of Saimiri, although Abeta40 tends to predominate in larger arterioles; 3) CAA and parenchymal plaques overlap to a considerable degree in most affected brain areas, and are distributed symmetrically in the two hemispheres; 4) Both CAA and plaques are particularly abundant in rostral regions and comparatively sparse in the occipital lobe; 5) Capillaries are especially vulnerable to CAA in squirrel monkeys; and 6) When CAA is severe, it is associated with a small, but significant, increase in other vasculopathies, including microhemorrhage, fibrinoid extravasation and focal gliosis. These findings, in the context of genetic, vascular and immunologic similarities between squirrel monkeys and humans, support the squirrel monkey as a biologically advantageous model for studying the basic biology of idiopathic, age-related CAA, and for testing emerging therapies for human beta-amyloidoses such as Alzheimer's disease.

Decreased expression of lysyl hydroxylase 2 (LH2) in skin fibroblasts from three Ehlers-Danlos patients does not result from mutations in either the coding or proximal promoter region of the LH2 gene.

The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of inherited connective tissue disorders characterized by tissue fragility, hyperelasticity of the skin and joint hypermobility. This phenotype, accompanied by kyphoscoliosis and/or ocular fragility, is present in patients with the autosomal recessive type VI form of EDS. These patients have significantly decreased levels of lysyl hydroxylase (LH) activity, due to mutations in the LH1 gene. LH hydroxylates specific lysine residues in the collagen molecule that are precursors for the formation of cross-links which provide collagen with its tensile strength. No disorder has been directly linked to decreased expression of LH2 and LH3, two other isoforms of LH. This study describes 3 patients with mixed phenotypes of EDS, who have significantly decreased mRNAs for LH2, but normal levels of LH1 and LH3 mRNAs, in their skin fibroblasts. In contrast to the effect of LH1 deficiency in EDS VI patients, the decreased expression of LH2 does not affect LH activity, bifunctional collagen cross-links (measured after reduction as dihydroxylysinonorleucine (DHLNL) and hydroxylysinonorleucine (HLNL)), or helical lysine hydroxylation in these cell lines. Sequence analysis of full length LH2 cDNAs and 1kb of the promoter region of LH2 does not show mutations that could explain the decreased expression of LH2. These results suggest that the deficiency of LH2 in these fibroblasts may be caused by changes in other factors required for the expression of LH2.

Expression of multidrug transporters in dysembryoplastic neuroepithelial tumors causing intractable epilepsy.

OBJECTIVE: Dysembryoplastic neuroepithelial tumors (DNT) are relatively benign brain lesions that often cause medically intractable epilepsy. There is mounting evidence that multidrug transporters such as P-glycoprotein (P-gp) or multidrug resistance-associated proteins (MRP) play an important role in the development of resistance to antiepileptic drugs (AED). MATERIAL AND METHODS: In the present study, we examined the expression of several multidrug transporters in 14 cases of DNT. The peritumoral brain tissue as well as 9 cases of arteriovenous malformations (AVM) served as controls. P-gp, MRP2, MRP5 and breast cancer resistance protein (BCRP) expression was evaluated qualitatively and quantitatively using immunohistochemistry. RESULTS: All transporters were overexpressed quantitatively in DNT, but each revealed a different labeling pattern. P-gp and BCRP were predominantly located in the endothelium of brain vessels. MRP5 was detected primarily in endothelial cells, but notably also in neurons. The expression of P-gp, MRP2 and MRP5 was low in AVM, whereas BCRP demonstrated strong staining. Examination of MDR1 gene polymorphisms revealed no correlation with P-gp expression whereas the MRP2 exon 10 G1249A polymorphism was associated with different MRP2 labelling. CONCLUSIONS: Our results show that multidrug transporters are overexpressed in DNT. This finding supports the view that several of these transport proteins may play an important role in the mechanisms of drug resistance in epileptic brain tissue.

Heterogeneous basis of the type VIB form of Ehlers-Danlos syndrome (EDS VIB) that is unrelated to decreased collagen lysyl hydroxylation.

Skin fibroblasts from the majority of patients with the clinical diagnosis of Ehlers-Danlos syndrome type VI (EDS VI; kyphoscoliosis type), have significantly decreased lysyl hydroxylase (LH) activity due to mutations in the LH1 gene (classified as EDS VIA: OMIM no. 225400). A rare condition exists in which patients are clinically similar but have normal levels of LH activity (designated EDS VIB: OMIM no. 229200). To define the biochemical defect, we have examined cultured fibroblasts from four EDS VIB patients for changes in the levels of the mRNAs for LH1, LH2, and LH3, collagen cross-linking patterns, and the extent of lysine hydroxylation of type I collagen alpha chains. Although normal levels of LH1 mRNA were observed in all four patients, in two patients the levels of LH2 mRNA were decreased by >50%, and a similar decrease was observed in LH3 mRNA in the other two patients. A distinct pattern of collagen cross-links, indicative of decreased lysyl hydroxylation, could be identified in EDS VIA patients, but there was no clear correlation between collagen cross-link pattern and changes in the individual LH mRNAs in EDS VIB patients. Linkage to tenascin-X was excluded in these patients. This study suggests that the basis for this form of EDS VI is genetically heterogeneous, and that alternative pathways in addition to lysine hydroxylation of collagen may be affected.

Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery.

Following cerebral ischemia, perilesional astrocytes and activated microglia form a glial scar that hinders the genesis of new axons and blood vessels in the infarcted region. Since glial reactivity is chronically augmented in the normal aging brain, the authors hypothesized that postischemic gliosis would be temporally abnormal in aged rats compared to young rats. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague Dawley rats. The functional outcome was assessed in neurobehavioral tests at 3, 7, 14, and 28 days after surgery. Brain tissue was immunostained for microglia, astrocytes, oligodendrocytes, and endothelial cells. Behaviorally, aged rats were more severely impaired by stroke and showed diminished functional recovery compared with young rats. Histologically, a gradual activation of both microglia and astrocytes that peaked by days 14 to 28 with the formation of a glial scar was observed in young rats, whereas aged rats showed an accelerated astrocytic and microglial reaction that peaked during the first week after stroke. Oligodendrocytes were strongly activated at early stages of infarct development in all rats, but this activation persisted in aged rats. Therefore, the development of the glial scar was abnormally accelerated in aged rats and coincided with the stagnation of recovery in these animals. These results suggest that a temporally anomalous gliotic reaction to cerebral ischemia in aged rats leads to the premature formation of scar tissue that impedes functional recovery after stroke.

Cerebral beta-amyloid deposition is augmented by the -491AA promoter polymorphism in non-demented elderly individuals bearing the apolipoprotein E epsilon4 allele.

The apolipoprotein E epsilon4 allele (APOE, gene; apoE, protein) is widely accepted as a risk factor for Alzheimer's disease (AD). Our previous studies found that APOEepsilon4 promotes AD pathogenesis by fostering the early deposition of the amyloidogenic peptide Abeta in the aging brain. Recent reports suggest that polymorphisms in the upstream promoter region of APOE differentially affect the production of apoE and also may have an important influence on the probability of developing AD. In this study, we asked whether APOE promoter -491 (A/T) variants interact with APOE polymorphisms to modulate the degree of beta-amyloid- and tau-related pathology in the medial temporal lobe of the non-demented elderly. Our results confirm that APOEepsilon4 is associated with increased formation of senile plaques, cerebrovascular amyloid, and neurofibrillary tangles in the medial temporal lobe. We also found that homozygosity for A at position -491 of the APOE promoter (-491AA) correlates with increased Abeta17-24 and Abeta42 deposition in APOEepsilon4-positive cases, but not in cases lacking the epsilon4 allele. In comparison, Abeta burden is significantly less in epsilon4 carriers with the -491AT and -491TT promoter allelotypes. There was no effect of -491 polymorphisms on Abeta40 deposition (which is relatively sparse in the non-demented elderly), on the number of activated microglia, or on the amount of neurofibrillary tangles. We conclude that the amyloidogenic effects of apoE4 are exacerbated by polymorphisms in the APOE promoter that enhance apoE production.

Modeling Alzheimer's disease and other proteopathies in vivo: is seeding the key?

Protein misfolding and aberrant polymerization are salient features of virtually all central neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, triplet repeat disorders, tauopathies, and prion diseases. In many instances, a single amino acid change can predispose to disease by increasing the production and/or changing the biophysical properties of a specific protein. Possible pathogenic similarities among the cerebral proteopathies suggest that therapeutic agents interfering with the proteopathic cascade might be effective against a wide range of diseases. However, testing compounds preclinically will require disease-relevant animal models. Numerous transgenic mouse models of beta-amyloidosis, tauopathy, and other aspects of AD have now been produced, but none of the existing models fully recapitulates the pathology of AD. In an attempt to more faithfully replicate the human disease, we infused dilute AD-brain extracts into Tg2576 mice at 3-months of age (i.e. 5-6 months prior to the usual onset of beta-amyloid deposition). We found that intracerebral infusion of AD brain extracts results in: 1). Premature deposition of beta-amyloid in eight month-old, beta-amyloid precursor protein ( betaAPP)-transgenic mice (Kane et al., 2000); 2). augmented amyloid load in the injected hemisphere of 15 month-old transgenic mice; 3). evidence for the spread of pathology to other brain areas, possibly by neuronal transport mechanisms; and 4). tau hyperphosphorylation (but not neurofibrillary pathology) in axons passing through the injection site. The seeding of beta-amyloid in vivo by AD brain extracts suggests pathogenic similarities between beta-amyloidoses such as AD and other cerebral proteopathies such as the prionoses, and could provide a new model for studying the proteopathic cascade and its neuronal consequences in neurodegenerative diseases.

Activated microglia do not mediate the early deposition of Abeta in carriers of the apolipoprotein Eepsilon4 allele.

Activated microglia are a prominent component of the senile plaques in end-stage Alzheimer's disease, but whether microglia contribute to the initiation of the lesions remains unknown. In a previous postmortem study of non-demented elderly cases, we found that amyloidogenesis is advanced by at least 10 years in carriers of the apoEepsilon4 allele. To determine whether microglia are involved in the initial stages of beta-amyloid pathogenesis and whether apoE genotype influences microglial activation, we quantified HLA-DR-immunoreactive microglia in the medial temporal lobe of 229 non-demented humans of various APOE genotypes who had died between 50 and 91 years of age. Our results show that the number of HLA-DR-immunoreactive microglia increases with advancing age in both the gray matter and the white matter. In contrast to amyloid plaques and neurofibrillary tangles, there is no significant correlation between apoE genotype and density of microglia, although apoEepsilon4 homozygotes tended to have more microglia than did other apoE groups. In sections double-immunostained for Abeta and activated microglia, activated microglia were associated with dense-cored plaques but not with diffuse plaques, suggesting that microglial activation is a relatively late event in the genesis of beta-amyloid. Activation of microglia thus appears not to be the initial impetus for Abeta-deposition in the elderly.

A prospective study of the removal rate of imaged breast lesions by an 11-gauge vacuum-assisted biopsy probe system.

BACKGROUND: More than 1,000,000 breast biopsies are performed each year as a result of abnormalities identified by imaging techniques. This prospective study was designed to determine whether complete removal of the imaged evidence of an abnormal mammogram or ultrasonogram could be achieved with percutaneous image-guided procedures using an 11-gauge vacuum-assisted biopsy probe. METHODS: Forty-five women over the age of 18 years entered the study; 50 breast lesions were identified by ultrasonography or mammography. Biopsies were obtained using an 11-gauge vacuum-assisted probe. At 6 months after biopsy, ultrasonography or mammography examinations of the biopsy site were performed. RESULTS: Forty-five lesions (90%) were completely removed. At 6 months after biopsy, 82% of the sites were lesion free. The percentage of nonrecurring lesions at 6 months after surgery was inversely related to the size of the original lesion. CONCLUSION: This device allows biopsies to be successfully combined with complete removal of the imaged lesion in a one-step minimally invasive procedure.

Translocation (2;14) associated with complex rearrangements of the Ig heavy chain in non-Hodgkin lymphoma.

Cytogenetic analysis of a patient with non-Hodgkin lymphoma revealed the following karyotype: 49,XXX,t(2;14)(q21;q32),+4,+8,del(13)(q14q21). Southern blot analysis with an Ig region probe showed non-productive rearrangements indicative of a translocation involving the Ig locus. However, molecular cloning of the abnormal rearrangements did not show novel sequences derived from chromosome 2 but showed that the BCL-6 gene was juxtaposed to the IgH enhancer. Three further clones with abnormal rearrangements involving the Ig locus, particularly Iggamma3, were isolated. This suggests that the mature lymphoid cells, in this patient, were capable of undergoing indiscriminate switch cleavage and religation.

Augmented senile plaque load in aged female beta-amyloid precursor protein-transgenic mice.

Transgenic mice (Tg2576) overexpressing human beta-amyloid precursor protein with the Swedish mutation (APP695SWE) develop Alzheimer's disease-like amyloid beta protein (Abeta) deposits by 8 to 10 months of age. These mice show elevated levels of Abeta40 and Abeta42, as well as an age-related increase in diffuse and compact senile plaques in the brain. Senile plaque load was quantitated in the hippocampus and neocortex of 8- to 19-month-old male and female Tg2576 mice. In all mice, plaque burden increased markedly after the age of 12 months. At 15 and 19 months of age, senile plaque load was significantly greater in females than in males; in 91 mice studied at 15 months of age, the area occupied by plaques in female Tg2576 mice was nearly three times that of males. By enzyme-linked immunosorbent assay, female mice also had more Abeta40 and Abeta42 in the brain than did males, although this difference was less pronounced than the difference in histological plaque load. These data show that senescent female Tg2576 mice deposit more amyloid in the brain than do male mice, and may provide an animal model in which the influence of sex differences on cerebral amyloid pathology can be evaluated.