Publisher Correction: Anti-AMPA GluA3 antibodies in Frontotemporal dementia: a new molecular target.

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Anti-AMPA GluA3 antibodies in Frontotemporal dementia: a new molecular target.

Frontotemporal Dementia (FTD) is a neurodegenerative disorder mainly characterised by Tau or TDP43 inclusions. A co-autoimmune aetiology has been hypothesised. In this study, we aimed at defining the pathogenetic role of anti-AMPA GluA3 antibodies in FTD. Serum and cerebrospinal fluid (CSF) anti-GluA3 antibody dosage was carried out and the effect of CSF with and without anti-GluA3 antibodies was tested in rat hippocampal neuronal primary cultures and in differentiated neurons from human induced pluripotent stem cells (hiPSCs). TDP43 and Tau expression in hiPSCs exposed to CSF was assayed. Forty-one out of 175 screened FTD sera were positive for the presence of anti-GluA3 antibodies (23.4%). FTD patients with anti-GluA3 antibodies more often presented presenile onset, behavioural variant FTD with bitemporal atrophy. Incubation of rat hippocampal neuronal primary cultures with CSF with anti-GluA3 antibodies led to a decrease of GluA3 subunit synaptic localization of the AMPA receptor (AMPAR) and loss of dendritic spines. These results were confirmed in differentiated neurons from hiPSCs, with a significant reduction of the GluA3 subunit in the postsynaptic fraction along with increased levels of neuronal Tau. In conclusion, autoimmune mechanism might represent a new potentially treatable target in FTD and might open new lights in the disease underpinnings.

Inhibition of ceramide de novo synthesis as a postischemic strategy to reduce myocardial reperfusion injury.

The injury caused by myocardial reperfusion after ischemia can be contained by interventions aimed at reducing the inflammation and the oxidative stress that underlie exacerbation of tissue damage. Sphingolipids are a class of structural and signaling lipid molecules; among them, the inflammation mediator ceramide accumulates in the myocardium upon ischemia/reperfusion. Here, we show that, after transient coronary occlusion in mice, an increased de novo ceramide synthesis takes place at reperfusion in the ischemic area surrounding necrosis (area at risk). This correlates with the enhanced expression of the first and rate-limiting enzyme of the de novo pathway, serine palmitoyltransferase (SPT). The intraventricular administration at reperfusion of myriocin, an inhibitor of SPT, significantly protected the area at risk from damage, reducing the infarcted area by 40.9 % relative to controls not treated with the drug. In the area at risk, myriocin downregulated ceramide, reduced the content in other mediators of inflammation and reactive oxygen species, and activated the Nrf2-HO1 cytoprotective response. We conclude that an enhanced ceramide synthesis takes part in ischemia/reperfusion injury and that myriocin treatment can be proposed as a strategy for myocardial pharmacological postconditioning.

Italian Frontotemporal Dementia Network (FTD Group-SINDEM): sharing clinical and diagnostic procedures in Frontotemporal Dementia in Italy.

In the prospect of improved disease management and future clinical trials in Frontotemporal Dementia, it is desirable to share common diagnostic procedures. To this aim, the Italian FTD Network, under the aegis of the Italian Neurological Society for Dementia, has been established. Currently, 85 Italian Centers involved in dementia care are part of the network. Each Center completed a questionnaire on the local clinical procedures, focused on (1) clinical assessment, (2) use of neuroimaging and genetics; (3) support for patients and caregivers; (4) an opinion about the prevalence of FTD. The analyses of the results documented a comprehensive clinical and instrumental approach to FTD patients and their caregivers in Italy, with about 1,000 newly diagnosed cases per year and 2,500 patients currently followed by the participating Centers. In analogy to other European FTD consortia, future aims will be devoted to collect data on epidemiology of FTD and its subtypes and to provide harmonization of procedures among Centers.

Microglia convert aggregated amyloid-ß into neurotoxic forms through the shedding of microvesicles.

Alzheimer's disease (AD) is characterized by extracellular amyloid-ß (Aß) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Aß species, rather than insoluble fibrils, are the most toxic forms of Aß. Preventing soluble Aß formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Aß species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Aß forms trafficked to MVs after Aß internalization into microglia. MV neurotoxicity was neutralized by the Aß-interacting protein PrP and anti-Aß antibodies, which prevented binding to neurons of neurotoxic soluble Aß species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease.

Autophagy in term normal human placentas.

Autophagy is an inducible catabolic process that responds to environment and is essential for cell survival during stress, starvation and hypoxia. Its function in the human placenta it is not yet understood. We collected 14 placentas: 7 at vaginal delivery and 7 at elective caesarean section after uneventful term pregnancies. The presence of autophagy was assessed in different placental areas by immunoblotting, immunohistochemistry and electron microscopy. We found that autophagy is significantly higher in placentas obtained from cesarean section than in those from vaginal delivery. Moreover there is a significant inverse relationship between autophagy and umbilical arterial glucose concentration.

TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers.

OBJECTIVES: To determine whether TMEM106B single nucleotide polymorphisms (SNPs) are associated with frontotemporal lobar degeneration (FTLD) in patients with and without mutations in progranulin (GRN) and to determine whether TMEM106B modulates GRN expression. METHODS: We performed a case-control study of 3 SNPs in TMEM106B in 482 patients with clinical and 80 patients with pathologic FTLD-TAR DNA-binding protein 43 without GRN mutations, 78 patients with FTLD with GRN mutations, and 822 controls. Association analysis of TMEM106B with GRN plasma levels was performed in 1,013 controls and TMEM106B and GRN mRNA expression levels were correlated in peripheral blood samples from 33 patients with FTLD and 150 controls. RESULTS: In our complete FTLD patient cohort, nominal significance was identified for 2 TMEM106B SNPs (top SNP rs1990622, p(allelic) = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected p(allelic) = 0.0009), where there was a highly significant decrease in the frequency of homozygote carriers of the minor alleles of all TMEM106B SNPs (top SNP rs1990622, CC genotype frequency 2.6% vs 19.1%, corrected p(recessive) = 0.009). We further identified a significant association of TMEM106B SNPs with plasma GRN levels in controls (top SNP rs1990622, corrected p = 0.002) and in peripheral blood samples a highly significant correlation was observed between TMEM106B and GRN mRNA expression in patients with FTLD (r = -0.63, p = 7.7 × 10(-5)) and controls (r = -0.49, p = 2.2 × 10(-10)). CONCLUSIONS: In our study, TMEM106B SNPs significantly reduced the disease penetrance in patients with GRN mutations, potentially by modulating GRN levels. These findings hold promise for the development of future protective therapies for FTLD.

The new Alzheimer's criteria in a naturalistic series of patients with mild cognitive impairment.

To test the validity of the new diagnostic criteria for Alzheimer's disease (AD) in a naturalistic series of patients with mild cognitive impairment (MCI). Ninety consecutive MCI patients were enrolled in a longitudinal study on the natural history of cognitive impairment. Medial temporal (MT) atrophy on MRI was defined as hippocampal volume below the fifth percentile of the distribution in healthy elders, abnormal CSF was based on Sjogren's cutoffs for Abeta42 and tau, and temporoparietal hypometabolism on 18F-FDG PET based on Herholz's t sum score. Patients were followed clinically to detect conversion to AD (MCI-AD), non-AD dementia (MCI-nAD), or no conversion (MCI-NC). The 24 MCI-AD and 15 MCI-nAD patients had sociodemographic, clinical, and neuropsychological baseline features similar to the 51 MCI-NC patients. All MCI patients with MT atrophy converted to AD, as did all those with abnormal CSF, but only 48 and 35% of those without MT atrophy or abnormal CSF converted (p on logrank test = 0.0007 and 0.001). Prediction of AD conversion was enhanced when positivity to either MT atrophy or abnormal CSF was considered, with only 15% of those MCI patients negative on both converting to AD (p < 0.0005). Markers were not predictive of non-AD dementia conversion. The accuracy of either MT atrophy or abnormal CSF in discriminating MCI-AD from MCI-NC was good (AUC 0.82, 95% CI 0.70-0.95). MT atrophy and abnormal CSF are the single most robust predictors of conversion to AD in MCI patients, and their combination enhances prediction. AD markers are not predictive of conversion to non-AD dementia.

The CST3 B haplotype is associated with frontotemporal lobar degeneration.

BACKGROUND AND PURPOSE: Frontotemporal lobar degeneration (FTLD) is a common cause of early-onset dementia. Given the role of cystatin C in brain neurodegeneration and neuroregeneration, the aim of this study was to determine whether the cystatin C gene (CST3) was genetically associated with FTLD. METHODS: Hundred and eighty-six FTLD patients and 457 controls underwent CST3 analysis by PCR and KspI enzyme digestion. RESULTS: In FTLD patients negative for the presence of PGRN mutations, we found an over-representation of the CST3 haplotype B [odds ratio (OR = 1.619, P = 0.002)] and of AB/BB genotypes (OR = 1.704, P = 0.008) in FTLD patients. CONCLUSIONS: The present study indicated the CST3 B haplotype as a putative risk factor for FTLD in PGRN mutations negative patients. The reduced level of cystatin C, previously associated with the B haplotype, might represent the molecular factor responsible for the increased risk. Long-term depletion of neurotrophic factors, such as cystatin C and progranulin proteins, seem to be a common theme in FTLD: boosting the expression of such proteins might be a promising therapeutic strategy for FTLD.

Mapping the effect of APOE epsilon4 on gray matter loss in Alzheimer's disease in vivo.

Previous studies suggest that in Alzheimer's disease (AD) the Apolipoprotein E (APOE) epsilon4 allele is associated with greater vulnerability of medial temporal lobe structures. However, less is known about its effect on the whole cortical mantle. Here we aimed to identify APOE-related patterns of cortical atrophy in AD using an advanced computational anatomy technique. We studied 15 AD patients carriers (epsilon4+, age: 72+/-10 SD years, MMSE: 20+/-3 SD) and 14 non-carriers (epsilon4-, age: 69+/-9, MMSE: 20+/-5) of the epsilon4 allele and compared them to 29 age-and-sex matched controls (age: 70+/-9, MMSE: 28+/-1). Each subject underwent a clinical evaluation, a neuropsychological battery, and high-resolution MRI. UCLA's cortical pattern matching technique was used to identify regions of local cortical atrophy. epsilon4+ and epsilon4- patients showed similar performance on neuropsychological tests (p>.05, t-test). Diffuse cortical atrophy was detected for both epsilon4+ (p=.0001, permutation test) and epsilon4- patients (p=.0001, permutation test) relative to controls, and overall gray matter loss was about 15% in each patients group. Differences in gray matter loss between carriers and non-carriers mapped to the temporal cortex and right occipital pole (20% greater loss in carriers) and to the posterior cingulate, left orbitofrontal and dorsal fronto-parietal cortex (5-15% greater loss in non-carriers). APOE effect in AD was not significant (p>.74, ANOVA), but a significant APOE by region (temporal vs fronto-parietal cortex) interaction was detected (p=.002, ANOVA), in both early and late-onset patients (p<.05, ANOVA). We conclude that the epsilon4 allele modulates disease phenotype in AD, being associated with a pattern of differential temporal and fronto-parietal vulnerability.

Longitudinal prognostic value of serum "free" copper in patients with Alzheimer disease.

BACKGROUND: Serum copper not bound to ceruloplasmin ("free") appears slightly elevated in patients with Alzheimer disease (AD). We explored whether a deregulation of the free copper pool can predict AD clinical worsening. METHODS: We assessed levels of copper, iron, zinc, transferrin, ceruloplasmin, peroxides, total antioxidant capacity, free copper, and apolipoprotein E genotype in 81 patients with mild or moderate AD, mean age 74.4, SD = 7.4 years, clinically followed up after 1 year. The association among biologic variables under study and Mini-Mental State Examination (MMSE) (primary outcome), activities of daily living (ADL), and instrumental activities of daily living (IADL) (secondary outcomes) performed at study entry and after 1 year were analyzed by multiple regression. RESULTS: Free copper predicted the annual change in MMSE, adjusted for the baseline MMSE by means of a linear regression model: it raised the explained variance from 2.4% (with only sex, age, and education) to 8.5% (p = 0.026). When the annual change in MMSE was divided into < 3 or > or = 3 points, free copper was the only predictor of a more severe decline (predicted probability of MMSE worsening 23%: odds ratio = 1.23; 95% confidence interval = 1.03-1.47; p = 0.022). Hyperlipidemic patients with higher levels of free copper seemed more prone to worse cognitive impairment. Free copper at baseline correlated with the ADL and IADL clinical scales scores at 1 year. CONCLUSIONS: These results show an association between copper deregulation and unfavorable evolution of cognitive function in Alzheimer disease. Further research is needed to establish whether copper is an independent risk factor for cognitive decline.

The NOS3 G894T (Glu298Asp) polymorphism is a risk factor for frontotemporal lobar degeneration.

BACKGROUND AND AIMS: Neuronal nitric oxide synthase (NOS)1 C276T polymorphism was shown to increase the risk for frontotemporal lobar degeneration (FTLD). In the brain, both NOS1 and NOS3 (endothelial isoform) have been detected. The distribution of NOS3 G894T (Glu298Asp) and T-786C single nucleotide polymorphisms (SNPs) was analyzed in a population of 222 patients with FTLD compared with 218 age-matched controls to determine whether they could influence the susceptibility to develop the disease. RESULTS: A statistically significant increased frequency of the NOS3 G894T SNP was observed in patients as compared with controls (40.0 vs. 31.4%, P = 0.011, OR: 1.65, CI: 1.13-2.42). Conversely, the distribution of the T-786C SNP was similar in patients and controls. No differences were observed stratifying according to gender. DISCUSSION: The NOS3 G894T polymorphism likely acts as risk factor for sporadic FTLD, but studies in larger populations are needed to confirm these preliminary findings.

Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration.

BACKGROUND: Mutations in the progranulin gene (PGRN) were identified as the causal mechanism underlying frontotemporal lobar degeneration (FTLD). Most of these mutations are predicted to create null alleles leading to a 50% loss of progranulin transcript. METHODS: Patients underwent clinical and neurologic examination at the Memory Clinic of the IRCCS S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy. We enrolled affected (n = 6) and unaffected at risk members (n = 73) of families carrying the FTLD associated progranulin Leu271LeufsX10 mutation; additionally, we included subjects affected by sporadic/familial FTLD (n = 65), controls (n = 75), and a family carrying the tau P301L mutation. The presence of mutations in PGRN and MAPT genes was investigated by direct sequencing of exonic and flanking intronic regions. Progranulin plasma and CSF levels were measured using ELISA. RESULTS: We demonstrated that progranulin protein is strongly reduced (up to 3.93-fold) both in plasma and CSF of affected and unaffected subjects carrying mutations in progranulin gene (PGRN Leu271LeufsX10 and Q341X). We established a plasma progranulin protein cutoff level of 74.4 ng/mL that identifies, with specificity and sensitivity of 100%, mutation carriers among unaffected subjects. In FTLD, values

Decreased plasma levels of soluble receptor for advanced glycation end products in mild cognitive impairment.

Growing evidence advanced the idea that the soluble form of the receptor for advanced glycation end-products (sRAGE) might serve as a risk marker for several disorders including Alzheimer disease. We found a reduced level of circulating sRAGE in patients with mild cognitive impairment (MCI). The reduction of sRAGE in MCI, as well as the anticipation of the disease in patients with the lowest sRAGE levels (

Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells.

Resveratrol, a polyphenol found in grapes and other fruit and vegetables, is a powerful chemopreventive and chemotherapeutic molecule potentially of interest for the treatment of breast cancer. The human breast cancer cell line MCF-7, which is devoid of caspase-3 activity, is refractory to apoptotic cell death after incubation with resveratrol. Here we show that resveratrol arrests cell proliferation, triggers death and decreases the number of colonies of cells that are sensitive to caspase-3-dependent apoptosis (MCF-7 casp-3) and also those that are unresponsive to it (MCF-7vc). We demonstrate that resveratrol (i) acts via multiple pathways to trigger cell death, (ii) induces caspase-dependent and caspase-independent cell death in MCF-7 casp-3 cells, (iii) induces only caspase-independent cell death in MCF-7vc cells and (iv) stimulates macroautophagy. Using BECN1 and hVPS34 (human vacuolar protein sorting 34) small interfering RNAs, we demonstrate that resveratrol activates Beclin 1-independent autophagy in both cell lines, whereas cell death via this uncommon form of autophagy occurs only in MCF-7vc cells. We also show that this variant form of autophagic cell death is blocked by the expression of caspase-3, but not by its enzymatic activity. In conclusion, this study reveals that non-canonical autophagy induced by resveratrol can act as a caspase-independent cell death mechanism in breast cancer cells.

Insulin-like growth factor binding protein-3 induces angiogenesis through IGF-I- and SphK1-dependent mechanisms.

Angiogenesis is critical for development and repair, and is a prominent feature of many pathological conditions. Based on evidence that insulin-like growth factor binding protein (IGFBP)-3 enhances cell motility and activates sphingosine kinase (SphK) in human endothelial cells, we have investigated whether IGFBP-3 plays a role in promoting angiogenesis. IGFBP-3 potently induced network formation by human endothelial cells on Matrigel. Moreover, it up-regulated proangiogenic genes, such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP)-2 and -9. IGFBP-3 even induced membrane-type 1 MMP (MT1-MMP), which regulates MMP-2 activation. Decreasing SphK1 expression by small interfering RNA (siRNA), blocked IGFBP-3-induced network formation and inhibited VEGF, MT1-MMP but not IGF-I up-regulation. IGF-I activated SphK, leading to sphingosine-1-phosphate (S1P) formation. The IGF-I effect on SphK activity was blocked by specific inhibitors of IGF-IR, PI3K/Akt and ERK1/2 phosphorylation. The disruption of IGF-I signaling prevented the IGFBP-3 effect on tube formation, SphK activity and VEGF release. Blocking ERK1/2 signaling caused the loss of SphK activation and VEGF and IGF-I up-regulation. Finally, IGFBP-3 dose-dependently stimulated neovessel formation into subcutaneous implants of Matrigel in vivo. Thus, IGFBP-3 positively regulates angiogenesis through involvement of IGF-IR signaling and subsequent SphK/S1P activation.

Homocysteine and electroencephalographic rhythms in Alzheimer disease: a multicentric study.

High plasma concentration of homocysteine is an independent risk factor for Alzheimer's disease (AD), due to microvascular impairment and consequent neural loss [Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346(7):476-483]. Is high plasma homocysteine level related to slow electroencephalographic (EEG) rhythms in awake resting AD subjects, as a reflection of known relationships between cortical neural loss and these rhythms? To test this hypothesis, we enrolled 34 mild AD patients and 34 subjects with mild cognitive impairment (MCI). Enrolled people were then subdivided into four sub-groups of 17 persons: MCI and AD subjects with low homocysteine level (MCI- and AD-, homocysteine level <11 micromol/l); MCI and AD subjects with high homocysteine level (MCI+ and AD+, homocysteine level >or=11 micromol/l). Resting eyes-closed EEG data were recorded. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Results showed that delta (frontal and temporal), theta (central, frontal, parietal, occipital, and temporal), alpha 1 (parietal, occipital, and temporal), and alpha 2 (parietal and occipital) sources were stronger in magnitude in AD+ than AD- group. Instead, no difference was found between MCI- and MCI+ groups. In conclusion, high plasma homocysteine level is related to unselective increment of cortical delta, theta, and alpha rhythms in mild AD, thus unveiling possible relationships among that level, microvascular concomitants of advanced neurodegenerative processes, and synchronization mechanisms generating EEG rhythms.

[Metals and oxidative stress in Parkinson's disease from industrial areas with exposition to environmental toxins or metal pollution]. / Dismetabolismo dei metalli e stress ossidativo in pazienti con in Parkinson's disease di un'area industriale esposta ad inquinamento da metalli.

BACKGROUND: Parkinson's disease (PD) is characterized by a progressive degeneration of the nigrostriatal dopaminergic pathway resulting in movement disorders. PD is a complex disease, in which and environmental factors, as exposure to toxins or metals coul be involved. OBJECTIVE: To assess if serum metals (Cu, Fe, Zn), biological variables of their metabolism, total peroxides and antioxidants were abnormal in PD, in relation to environmental exposure. METHODS: We compared levels of serum copper, iron, zinc, ceruloplasmin and transferrin, peroxides, antioxidants (TRAP) in 65 PD patients coming from an Industrial zone highly exposed to metal pollution (Valcamonica) with measures from 28 PD patients from no metal pollution areas of the province of Brescia and 52 healthy controls coming from Valcamonica and 24 from the province of Brescia. RESULTS: PD patients had higher serum concentration of zinc than controls. Only in PD patients coming from Valcamonica levels of Cu were higher than in subjects coming from the province of Brescia. Moreover, In patients with PD levels of sieric Cu significantly correlated with score of the Unified Parkinson's Disease Rating Scale (UDPRS). CONCLUSIONS: Zinc seems to be higher in PD independently from the exposition to metal pollution. Perturbation of copper metabolism in PD seems to be related to exposition to environmental toxins or metal pollution and coul be involved in the progression of the disease itself.

Effects of estrogens on cognition and brain morphology: involvement of the cerebellum.

OBJECTIVES: Sex steroid hormones are implicated in the cognitive processes of the adult brain. Among studies reporting a positive effect of estrogen replacement therapy (ERT) on cognition, the most consistent evidence is that it enhances verbal memory and visuospatial functions. In the present study we investigated the effect of ERT on cognition and on brain morphology in healthy postmenopausal women, taking into account the distinction in current and past ERT users. METHODS: Participants were postmenopausal nondemented women recruited from the community: ERT users were 40 (23 current users, 17 past users), while never users were 43. Forty of recruited subjects gave consent to undergo 3D high resolution MRI (16 current users, 7 past users and 17 never users). Participants underwent MMSE and a battery of neuropsychological tests measuring memory, language, intelligence, attention and visuo-spatial abilities. RESULTS: The past users group outperformed the never users in four tests: Token test, WCST categories, attentional matrices and Rey's delayed list; the current users group outperformed the never users in the Rey's list test. ERT users had greater grey matter volumes mainly in the cerebellum, but an increase was observed also in the parietal and occipital cortex. CONCLUSIONS: ERT use appears to improve linguistic, attentive and planning abilities. Interestingly, the beneficial effects on cognition were detected mainly in the past users subgroup. Here we propose that the trophic effect of estrogens on cerebellum might account for the observed improvement in cognition.

Resveratrol and breast cancer risk.

Resveratrol is a non-flavonoid polyphenol that has attracted attention as a potential anticancer agent in vitro and in vivo, but scanty epidemiological data are available. We have therefore analysed the relation between dietary intake of resveratrol and breast cancer risk using data from a case-control study conducted between 1993 and 2003 in the Swiss Canton of Vaud on 369 cases and 602 controls. Compared with the lowest tertile of total resveratrol intake, the multivariate odds ratios (OR) were 0.50 for the intermediate and 0.39 for the highest tertile, and the trend in risk was significant. A significant inverse association was observed for resveratrol from grapes (OR = 0.64 and 0.55), but not for wine. The inverse relation between resveratrol and breast cancer risk was not explained by several potential confounding factors, including detailed allowance for alcohol intake, nor attributable to a non-specific favourable effect of fruit on breast cancer risk.