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1.  Intimate Partner Violence (IPV) During Pregnancy: A Pilot Intervention Program in Lima, Peru 
Journal of interpersonal violence  2010;25(11):2054-2076.
This pilot study examined the effectiveness of standard care and an empowerment intervention for abused pregnant women. Severe psychological abuse was most prevalent (42.2%) among this sample of women. Compared with women in the standard care group at the post-intervention survey, women in the empowerment group were more likely to hide money (44.6% vs. 34.3%), establish a code with family or friends (19.6% vs. 16.2%), ask neighbors to call police if violence began (6.9% vs. 1.0%), had available bank account numbers (17.1% vs. 3.1%), had valuable jewelry (8.4% vs. 3.8%), and had available a hidden bag with extra clothing (9.0% vs. 3.1%). However, there was no statistically significant difference in health-related quality of life, adoption of safety behaviors, and use of community resources between women in the two groups. Simply asking pregnant women about abuse and offering referral could potentially interrupt and prevent further abuse.
doi:10.1177/0886260509354517
PMCID: PMC3741342  PMID: 20145196
Intimate partner violence; Pregnant women; Intervention; Peru
2.  Association Between Intimate Partner Violence, Migraine and Probable Migraine 
Headache  2010;51(2):208-219.
Objective
Intimate partner violence (IPV) among women is a global public health problem. The association between childhood maltreatment and migraine is well established, but not the association between IPV and migraine. The aim of this cross-sectional study was to evaluate the relationship between type and severity of IPV and migraine in a large cohort of Peruvian women.
Methods
Women who delivered singleton infants (N=2,066) at the Instituto Nacional Materno Perinatal, Lima, Peru were interviewed during their post-partum hospital stay. Participants were queried about their lifetime experiences with headaches and migraine, and with physical and sexual violence. The International Classification of Headache Disorders (ICHD-2) diagnostic criteria were used to classify participants according to their migraine status. Questions on physical and sexual violence were adapted from the protocol of Demographic Health Survey Questionnaires and Modules: Domestic Violence Module and the World Health Organization (WHO) Multi-Country Study on Violence against Women. Depressive symptoms were assessed using the nine-item Patient Health Questionnaire Depression Subset. Logistic regression was used to estimate multivariate adjusted odds ratios (aOR) and 95% confidence intervals (CI).
Results
Compared with women without a history of violence, women with experiences of lifetime physical or sexual violence (aOR=1.44, 95% CI 1.19–1.75), physical violence only (aOR=1.36, 95% CI 1.10–1.68), sexual violence only (aOR=1.76, 95% CI 0.97–3.21) and both physical and sexual violence (aOR=1.61, 95% CI 1.12–2.31) had increased odds of any migraine after adjusting for maternal age, parity and access to basic foods. There was no gradient of increased odds of any migraine with severity of physical violence. The relationship between IPV and any migraine was strongest among women with depressive symptoms. The odds of any migraine was increased 2.25-fold (95% CI 1.75–2.28) among abused women who also had depressive symptoms compared with non-abused and non-depressed women. Associations from sensitivity analyses that segregated women according to probable migraine (ICHD-2 category 1.6.1) and migraine (ICHD-2 category 1.1) diagnoses were of similar magnitudes as those reported here for women with any migraine diagnoses. IPV, particularly sexual violence, appears to be a risk factor for migraine.
Conclusion
Our findings suggest the potential importance of considering a history of violence among migraineurs.
doi:10.1111/j.1526-4610.2010.01777.x
PMCID: PMC3662491  PMID: 20946432
3.  Analysis of autosomal genes reveals gene–sex interactions and higher total genetic risk in men with systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2011;71(5):694-699.
Objectives
Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci.
Methods
A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex–gene interaction was further validated using parametric and nonparametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients.
Results
A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P = 4.52×10−8) A significant sex–gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men.
Conclusions
The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.
doi:10.1136/annrheumdis-2011-200385
PMCID: PMC3324666  PMID: 22110124
4.  Fine Mapping of Xq28: Both MECP2 and IRAK1 Contribute to Risk for Systemic Lupus Erythematosus in Multiple Ancestral Groups 
Annals of the rheumatic diseases  2012;72(3):437-444.
Objectives
The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE.
Methods
We fine-mapped ≥136 SNPs in a ~227kb region on Xq28, containing IRAK1, MECP2 and 7 adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15,783 case-control subjects derived from 4 different ancestral groups.
Results
Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at P<5×10−8 with consistent association in subjects with African ancestry. Of these, 6 SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all 4 ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest P value in trans-ancestral meta-analysis (Pmeta=1.3×10−27, OR=1.43), and thus was considered to be the most-likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (P=0.0012) and healthy controls (P=0.0064).
Conclusion
These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.
doi:10.1136/annrheumdis-2012-201851
PMCID: PMC3567234  PMID: 22904263
Systemic Lupus Erythematosus; Gene Polymorphism; Xq28; IRAK1; MECP2
5.  Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus 
Arthritis and Rheumatism  2012;64(2):485-492.
Objective
Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis is established in lupus. We test for gene-gene interactions in a number of known lupus susceptibility loci.
Methods
Eighteen SNPs tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 lupus patients and 3,818 normal healthy controls of European descent. Epistasis was tested using a 2-step approach utilizing both parametric and non-parametric methods. The false discovery rate (FDR) method was used to correct for multiple testing.
Results
We detected and confirmed gene-gene interactions between the HLA region and CTLA4, IRF5, and ITGAM, and between PDCD1 and IL21 in lupus patients. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (Interaction odds ratio=1.19, z-score= 3.95, P= 7.8×10−5 (FDR≤0.05), PMDR= 5.9×10−45). Importantly, our data suggest that in lupus patients the presence of the HLA lupus-risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus-risk allele in IRF5 (rs2070197) by 17% and 16%, respectively (P= 0.0028 and 0.0047).
Conclusion
We provide evidence for gene-gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability.
doi:10.1002/art.33354
PMCID: PMC3268866  PMID: 21952918
6.  Identification of novel genetic susceptibility loci in African-American lupus patients using a candidate gene association study 
Arthritis and rheumatism  2011;63(11):3493-3501.
Objective
Candidate gene and genome-wide association studies have identified several disease susceptibility loci in lupus patients. These studies have been largely performed in European-derived and Asian lupus patients. In this study, we examine if some of these same susceptibility loci increase lupus risk in African-American individuals.
Methods
Single nucleotide polymorphisms tagging 15 independent lupus susceptibility loci were genotyped in a set of 1,724 lupus patients and 2,024 normal healthy controls of African-American descent. The loci examined included: PTPN22, FCGR2A, TNFSF4, STAT4, CTLA4, PDCD1, PXK, BANK1, MSH5 (HLA region), CFB (HLA region), C8orf13-BLK region, MBL2, KIAA1542, ITGAM, and MECP2/IRAK1.
Results
We provide the first evidence for genetic association between lupus and five susceptibility loci in African-American patients (C8orf13-BLK, BANK1, TNFSF4, KIAA1542 andCTLA4; P values= 8.0 × 10−6, 1.9 × 10−5, 5.7 × 10−5, 0.00099, 0.0045, respectively). Further, we confirm the genetic association between lupus and five additional lupus susceptibility loci (ITGAM, MSH5, CFB, STAT4, and FCGR2A; P values= 7.5 × 10−11, 5.2 × 10−8, 8.7 × 10−7, 0.0058, and 0.0070, respectively), and provide evidence for a genome-wide significance for the association between ITGAM and MSH5 (HLA region) for the first time in African-American lupus patients.
Conclusion
These findings provide evidence for novel genetic susceptibility loci for lupus in African-Americans and demonstrate that the majority of lupus susceptibility loci examined confer lupus risk across multiple ethnicities.
doi:10.1002/art.30563
PMCID: PMC3205224  PMID: 21792837
7.  Acute lymphoblastic leukemia and developmental biology 
Cell Cycle  2011;10(20):3473-3486.
The latest scientific findings in the field of cancer research are redefining our understanding of the molecular and cellular basis of the disease, moving the emphasis toward the study of the mechanisms underlying the alteration of the normal processes of cellular differentiation. The concepts best exemplifying this new vision are those of cancer stem cells and tumoral reprogramming. The study of the biology of acute lymphoblastic leukemias (ALLs) has provided seminal experimental evidence supporting these new points of view. Furthermore, in the case of B cells, it has been shown that all the stages of their normal development show a tremendous degree of plasticity, allowing them to be reprogrammed to other cellular types, either normal or leukemic. Here we revise the most recent discoveries in the fields of B-cell developmental plasticity and B-ALL research and discuss their interrelationships and their implications for our understanding of the biology of the disease.
doi:10.4161/cc.10.20.17779
PMCID: PMC3266177  PMID: 22031225
leukemia; hematopoietic development; leukemic stem cells; lymphopoiesis; developmental plasticity; B cells; stem cells; cancer; B-ALL
8.  Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus 
Annals of the rheumatic diseases  2011;70(10):1752-1757.
Objective
Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic loci also contribute to the clinical heterogeneity in lupus.
Materials and methods
4001 European-derived, 1547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria.
Results
Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0×10−6, OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22). All these associations are significant with a false discovery rate of <0.05 and pass the significance threshold using Bonferroni correction for multiple testing.
Conclusion
Significant associations were found between lupus clinical manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future.
doi:10.1136/ard.2011.154104
PMCID: PMC3232181  PMID: 21719445
9.  Fine mapping and trans-ethnic genotyping establish IL2/IL21 genetic association with lupus and localize this genetic effect to IL21 
Arthritis and rheumatism  2011;63(6):1689-1697.
Objective
Genetic association of the IL2/IL21 region at 4q27 has been previously reported in lupus and a number of autoimmune and inflammatory diseases. Herein, using a very large cohort of lupus patients and controls, we localize this genetic effect to the IL21 gene.
Methods
We genotyped 45 tag SNPs across the IL2/IL21 locus in two large independent lupus sample sets. We studied a European-derived set consisting of 4,248 lupus patients and 3,818 healthy controls, and an African-American set of 1,569 patients and 1,893 healthy controls. Imputation in 3,004 WTCCC additional control individuals was also performed. Genetic association between the genotyped markers was determined, and pair-wise conditional analysis was performed to localize the independent genetic effect in the IL2/IL21 locus in lupus.
Results
We established and confirmed the genetic association between IL2/IL21 and lupus. Using conditional analysis and trans-ethnic mapping, we localized the genetic effect in this locus to two SNPs in high linkage disequilibrium; rs907715 located within IL21 (OR=1.16 (1.10–1.22), P= 2.17 ×10−8), and rs6835457 located in the 3’-UTR flanking region of IL21 (OR= 1.11 (1.05–1.17), P= 9.35×10−5).
Conclusion
We have established the genetic association between lupus and IL2/IL21 with a genome-wide level of significance. Further, we localized this genetic association within the IL2/IL21 linkage disequilibrium block to IL21. If other autoimmune IL2/IL21 genetic associations are similarly localized, then the IL21 risk alleles would be predicted to operate in a fundamental mechanism that influences the course of a number of autoimmune disease processes.
doi:10.1002/art.30320
PMCID: PMC3106139  PMID: 21425124
10.  Early disease onset is predicted by a higher genetic risk for lupus and is associated with a more severe phenotype in lupus patients 
Annals of the rheumatic diseases  2010;70(1):151-156.
Background
Systemic lupus erythematosus (SLE) is a chronic, multiorgan, autoimmune disease that affects people of all ages and ethnicities.
Objectives
To explore the relationship between age at disease onset and many of the diverse manifestations of SLE. Additionally, to determine the relationship between age of disease onset and genetic risk in patients with SLE.
Methods
The relationship between the age at disease onset and SLE manifestations were explored in a multiracial cohort of 1317 patients. Patients with SLE were genotyped across 19 confirmed genetic susceptibility loci for SLE. Logistic regression was used to determine the relationships between the number of risk alleles present and age of disease onset.
Results
Childhood-onset SLE had higher odds of proteinuria, malar rash, anti-dsDNA antibody, haemolytic anaemia, arthritis and leucopenia (OR=3.03, 2.13, 2.08, 2.50, 1.89, 1.53, respectively; p values <0.0001, 0.0004, 0.0005, 0.0024, 0.0114, 0.045, respectively). In female subjects, the odds of having cellular casts were 2.18 times higher in childhood-onset than in adult-onset SLE (p=0.0027). With age of onset ≥50, the odds of having proteinuria, cellular casts, anti-nRNP antibody, anti-Sm antibody, anti-dsDNA antibody and seizures were reduced. However, late adult-onset patients with SLE have higher odds of developing photosensitivity than early adult-onset patients. Each SLE-susceptibility risk allele carried within the genome of patients with SLE increased the odds of having a childhood-onset disease in a race-specific manner: by an average of 48% in Gullah and 25% in African-Americans, but this was not significant in Hispanic and European-American lupus patients.
Conclusions
The genetic contribution towards predicting early-onset disease in patients with SLE is quantified for the first time. A more severe SLE phenotype is found in patients with early-onset disease in a large multi-racial cohort, independent of gender, race and disease duration.
doi:10.1136/ard.2010.141697
PMCID: PMC3034281  PMID: 20881011
11.  Depressive Symptoms and Migraine Comorbidity among Pregnant Peruvian Women 
Journal of affective disorders  2009;122(1-2):149-153.
Background
Migraine and depression are known to be comorbid conditions in non-pregnant women and men. However, the migraine-depression comorbidity among pregnant women, particularly women in developing countries has not been evaluated. Therefore, we evaluated the migraine-depressive symptom relationship in a large cohort of pregnant Peruvian women.
Methods
Women who delivered singleton infants (N=2,293) at the Instituto Nacional Materno Perinatal, Lima, Peru were interviewed during the postpartum hospital stay. Women were asked questions related to their lifetime and pregnancy experiences with headaches and migraines. Responses to these questions enabled the classification of “probable” and “strict” migraines according to the International Headache Society diagnostic criteria. Depressive symptoms were assessed using the nine-item Patient Health Questionnaire Depression Subset. Logistic regression procedures were used to estimate adjusted odds ratios (AORs) and 95% confidence intervals (CIs).
Results
Approximately 32% of the women reported a history of migraine, while 41% reported experiencing moderate to severe depressive symptoms during pregnancy. Compared with women without a history of migraine, women with strict migraine had AORs of 2.12 (95% CI 1.54–2.93), 1.85 (95% CI 1.16–2.96) and 2.23 (95% CI 1.08–4.62) for moderate, moderately severe and severe depressive symptoms, respectively.
Conclusion
This is the first report of a cross-sectional association between migraine and depressive symptoms in pregnant women. If our findings are confirmed, pregnant women with a history of migraine may benefit from increased vigilance for screening and treating depressive symptoms.
doi:10.1016/j.jad.2009.07.014
PMCID: PMC2835839  PMID: 19695709
Migraine; Depressive symptoms; Pregnant women; Peru
12.  Aspirin Therapy for Inhibition of Platelet Reactivity in the Presence of Erythrocytes in Patients with Vascular Disease 
Inhibition of erythrocyte (RBC) promotion of platelet reactivity could improve the antiplatelet effect of aspirin (ASA). We tested different ASA regimens for optimal inhibition of platelets and the effects of RBC in patients with a history of vascular diseases. Collagen-induced platelet activation (14C-5HT, TXA2 release) and platelet recruitment (proaggregatory activity of cell-free releasates from activated platelets) were measured in PRP, platelet-RBC (Hct 40%) and whole blood (WB) in 206 patients initially on 200–300 mg ASA/day. Their regimen was modified to bi-weekly 500 mg (loading dose, L) plus daily or twice-daily low-dose ASA (50 or 100 mg). TXA2 was inhibited with all regimens. Percentage of patients with suboptimal inhibition of platelet recruitment in WB was: 200–300 ASA/day (41%), L-50/day (87%), L-100/day (58%), L-50/twice-daily (39%) and L-100/twice-daily (20%; p<0.05 vs. other regimens). 14C-5HT release was inhibited to the greatest extent with L-100/twice-daily in PRP+RBC or WB (p<0.05 vs. other regimens) due to greater inhibition of the RBC prothrombotic effect. Compared to other ASA regimens, L-100 twice-daily (equivalent to 221 mg ASA/day in the 14 day cycle), reduced by >50% the proportion of patients with suboptimal inhibition of platelet recruitment in WB and inhibited 14C-5HT release to the greatest extent.
doi:10.1016/j.lab.2005.12.005
PMCID: PMC1600016  PMID: 16697769
aspirin; blood cells; platelets; erythrocytes; cardiovascular diseases; cerebrovascular disorders; thrombosis; ADP: adenosine 5′-diphosphate; ASA: acetylsalicylic acid; BID: twice-daily; 14C-5HT: 14C-serotonin; COX-1: cyclooxygenase-1; L: loading dose; OD: daily; PRP: platelet-rich plasma; RBC: erythrocyte; TXA2: thromboxane A2; WB: whole blood

Résultats 1-12 (12)