Genetic Modifiers of Age at Onset in Carriers of the G206A Mutation in PSEN1 With Familial Alzheimer Disease Among Caribbean Hispanics

IMPORTANCE The present study identified potential genetic modifiers that may delay or accelerate age at onset of familial Alzheimer disease (AD) by examining age at onset in PSEN1 mutation carrier families, and further investigation of these modifiers may provide insight into the pathobiology of AD and potential therapeutic measures. DESIGN, SETTING, AND PARTICIPANTS Using a subset of Caribbean Hispanic families that carry the PSEN1 p.G206A mutation, we performed a 2-stage genome study. The mutation carrier families from an ongoing genetic study served as a discovery set, and the cohort of those with LOAD served as a confirmation set. To identify candidate loci, we performed linkage analysis using 5 p.G206A carrier families (n = 56), and we also performed whole-exome association analysis using 31 p.G206A carriers from 26 families. To confirm the genetic modifiers identified from the p.G206A carrier families, we analyzed the GWAS data for 2888 elderly individuals with LOAD. All study participants were Caribbean Hispanics. RESULTS Linkage analysis of AD identified the strongest linkage support at 4q35 (LOD [logarithm of odds] score, 3.69), and the GWAS of age at onset identified variants on 1p13.1, 2q13, 4q25, and 17p11. In the confirmation stage, genewise analysis identified SNX25, PDLIM3, and 3 SH3 domain genes (SORBS2, SH3RF3, and NPHP1) to be significantly associated with LOAD. Subsequent allelic association analysis confirmed SNX25, PDLIM3, and SORBS2 as genetic modifiers of age at onset of EOAD and LOAD and provided modest support for SH3RF3 and NPHP1. CONCLUSIONS AND RELEVANCE Our 2-stage analysis revealed that SNX25, PDLIM3, and SORBS2 may serve as genetic modifiers of age at onset in both EOAD and LOAD

Further Examination of the Candidate Genes in Chromosome 12p13 Locus for Late-Onset Alzheimer Disease

A broad region on chromosome 12p13 has been intensely investigated for novel genetic variants associated with Alzheimer disease (AD). We examined this region with 23 microsatellite markers using 124 North European (NE) families and 209 Caribbean Hispanic families with late-onset AD (FAD). Significant evidence for linkage was present in a 5-cM interval near 20 cM in both the NE FAD (LOD = 3.5) and the Caribbean Hispanic FAD (LOD = 2.2) datasets. We further investigated these families and an independent NE case-control dataset using 14 single nucleotide polymorphisms (SNPs). The initial screening of the region at approximately 20 cM in the NE case-control dataset revealed significant association between AD and seven SNPs in several genes, with the strongest result for rs2532500 in TAPBPL (p = 0.006). For rs3741916 in GAPDH, the C allele, rather than the G allele as was observed by Li et al. (Proc Natl Acad Sci U S A 101(44):15688-15693, 2004), was the risk allele. When the two family datasets were examined, none of the SNPs were significant in NE families, but two SNPs were associated with AD in Caribbean Hispanics: rs740850 in NCAPD2 (p = 0.0097) and rs1060620 in GAPDH (p = 0.042). In a separate analysis combining the Caribbean Hispanic families and NE cases and controls, rs740850 was significant after correcting for multiple testing (empirical p = 0.0048). Subsequent haplotype analyses revealed that two haplotype sets-haplotype C-A at SNPs 6-7 within NCAPD2 in Caribbean Hispanics, and haplotypes containing C-A-T at SNPs 8-10 within GAPDH in Caribbean Hispanic family and NE case-control datasets-were associated with AD. Taken together, these SNPs may be in linkage disequilibrium with a pathogenic variant(s) on or near NCAPD2 and GAPD

Spray drying and process optimization of sour orange juice

In this study, production of sour orange juice powder utilizing a spray dryer was investigated. To prevent stickiness, maltodextrin DE 12 was used as a drying agent. While feed flow rate, feed temperature, and air flow rate were kept constant, inlet air temperature (120–160 °C) and maltodextrin content (maltodextrin dry solids/100 g feed mixture dry solids; 10–20%, w/w) were selected as the independent variables. Product properties investigated included ascorbic acid, volatile compounds, and moisture content. Ascorbic acid retention, volatiles retention, and moisture content were used in optimization of the process by response surface methodology. The optimum inlet air temperature and maltodextrin content were 156 °C and 20% w/w maltodextrin, respectively. This study revealed that by applying these optimal conditions, sour orange juice powder with 81.5% ascorbic acid retention, 5.5%, w/w moisture content, and 78% volatiles retention was produced

Ultra-rare mutations in SRCAP segregate in Caribbean Hispanic families with Alzheimer disease.

OBJECTIVE: To identify rare coding variants segregating with late-onset Alzheimer disease (LOAD) in Caribbean Hispanic families. METHODS: Whole-exome sequencing (WES) was completed in 110 individuals from 31 Caribbean Hispanic families without APOE ε4 homozygous carriers. Rare coding mutations segregating in families were subsequently genotyped in additional families and in an independent cohort of Caribbean Hispanic patients and controls. SRCAP messenger RNA (mRNA) expression was assessed in whole blood from mutation carriers with LOAD, noncarriers with LOAD, and healthy elderly controls, and also from autopsied brains in 2 clinical neuropathologic cohort studies of aging and dementia. RESULTS: Ten ultra-rare missense mutations in the Snf2-related CREBBP, activator protein (SRCAP), were found in 12 unrelated families. Compared with the frequency in Caribbean Hispanic controls and the Latino population in the Exome Aggregation Consortium, the frequency of SRCAP mutations among Caribbean Hispanic patients with LOAD was significantly enriched (p = 1.19e-16). mRNA expression of SRCAP in whole blood was significantly lower in mutation carriers with LOAD, while the expression in whole blood and in the brain was significantly higher in nonmutation carriers with LOAD. Brain expression also correlated with clinical and neuropathologic endophenotypes. CONCLUSIONS: WES in Caribbean Hispanic families with LOAD revealed ultra-rare missense mutations in SRCAP, a gene expressed in the brain and mutated in Floating-Harbor syndrome. SRCAP is a potent coactivator of the CREB-binding protein and a regulator of DNA damage response involving ATP-dependent chromatin remodeling. We hypothesize that increased expression in LOAD suggests a compensatory mechanism altered in mutation carriers

Fine Mapping of 10q and 18q for Familial Alzheimer's Disease in Caribbean Hispanics

Familial Alzheimer's disease (AD [MIM 104300]) has been a focus of intense investigation, primarily in Caucasian families from Europe and North America families. Although the late-onset form of familial AD, beginning after age 65 years, has been linked to regions on chromosomes 10q and 12p, the specific genetic variants have not yet been consistently identified. Using a unique cohort of families of Caribbean Hispanics ancestry, we screened the genome using 340 markers on 490 family members from 96 families with predominantly late-onset AD. We observed the strongest support for linkage on 18q (LOD=3.14). However, 17 additional markers (chromosomes 1-6, 8, 10, 12, and 14) exceeded a two-point LOD score of 1.0 under the affecteds-only autosomal dominant model or affected sibpair model. As we previously reported the fine-mapping effort on 12p showing modest evidence of linkage, we focused our fine-mapping efforts on two other candidate regions in the current report, namely 10q and 18q. We added 31 family members and eight additional Caribbean Hispanic families to fine map 10q and 18q. With additional microsatellite markers, the evidence for linkage for 18q strengthened near 112 cM, where the two-point LOD score for D18S541 was 3.37 and the highest NPL score in that region was 3.65 (P=0.000177). This narrow region contains a small number of genes expressed in the brain. However, at 10q (134-138 cM), the NPL score decreased from 3.15 (P=0.000486) to 2.1 (P=0.0218), but two broad peaks remained overlapping with previously reported peaks. Our results provide modest support for linkage on 10q and 12p in this cohort of Caribbean Hispanic families with familial Alzheimer's disease, and strong evidence for a new locus on 18

Implementing academic detailing for breast cancer screening in underserved communities

<p>Abstract</p> <p>Background</p> <p>African American and Hispanic women, such as those living in the northern Manhattan and the South Bronx neighborhoods of New York City, are generally underserved with regard to breast cancer prevention and screening practices, even though they are more likely to die of breast cancer than are other women. Primary care physicians (PCPs) are critical for the recommendation of breast cancer screening to their patients. Academic detailing is a promising strategy for improving PCP performance in recommending breast cancer screening, yet little is known about the effects of academic detailing on breast cancer screening among physicians who practice in medically underserved areas. We assessed the effectiveness of an enhanced, multi-component academic detailing intervention in increasing recommendations for breast cancer screening within a sample of community-based urban physicians.</p> <p>Methods</p> <p>Two medically underserved communities were matched and randomized to intervention and control arms. Ninety-four primary care community (<it>i.e</it>., not hospital based) physicians in northern Manhattan were compared to 74 physicians in the South Bronx neighborhoods of the New York City metropolitan area. Intervention participants received enhanced physician-directed academic detailing, using the American Cancer Society guidelines for the early detection of breast cancer. Control group physicians received no intervention. We conducted interviews to measure primary care physicians' self-reported recommendation of mammography and Clinical Breast Examination (CBE), and whether PCPs taught women how to perform breast self examination (BSE).</p> <p>Results</p> <p>Using multivariate analyses, we found a statistically significant intervention effect on the recommendation of CBE to women patients age 40 and over; mammography and breast self examination reports increased across both arms from baseline to follow-up, according to physician self-report. At post-test, physician involvement in additional educational programs, enhanced self-efficacy in counseling for prevention, the routine use of chart reminders, computer- rather than paper-based prompting and tracking approaches, printed patient education materials, performance targets for mammography, and increased involvement of nursing and other office staff were associated with increased screening.</p> <p>Conclusion</p> <p>We found some evidence of improvement in breast cancer screening practices due to enhanced academic detailing among primary care physicians practicing in urban underserved communities.</p

Rare Variants Imputation in Admixed Populations: Comparison Across Reference Panels and Bioinformatics Tools

BackgroundImputation has become a standard approach in genome-wide association studies (GWAS) to infer in silico untyped markers. Although feasibility for common variants imputation is well established, we aimed to assess rare and ultra-rare variants’ imputation in an admixed Caribbean Hispanic population (CH).MethodsWe evaluated imputation accuracy in CH (N = 1,000), focusing on rare (0.1% ≤ minor allele frequency (MAF) ≤ 1%) and ultra-rare (MAF &lt; 0.1%) variants. We used two reference panels, the Haplotype Reference Consortium (HRC; N = 27,165) and 1000 Genome Project (1000G phase 3; N = 2,504) and multiple phasing (SHAPEIT, Eagle2) and imputation algorithms (IMPUTE2, MACH-Admix). To assess imputation quality, we reported: (a) high-quality variant counts according to imputation tools’ internal indexes (e.g., IMPUTE2 “Info” ≥ 80%). (b) Wilcoxon Signed-Rank Test comparing imputation quality for genotyped variants that were masked and imputed; (c) Cohen’s kappa coefficient to test agreement between imputed and whole-exome sequencing (WES) variants; (d) imputation of G206A mutation in the PSEN1 (ultra-rare in the general population an more frequent in CH) followed by confirmation genotyping. We also tested ancestry proportion (European, African and Native American) against WES-imputation mismatches in a Poisson regression fashion.ResultsSHAPEIT2 retrieved higher percentage of imputed high-quality variants than Eagle2 (rare: 51.02% vs. 48.60%; ultra-rare 0.66% vs. 0.65%, Wilcoxon p-value &lt; 0.001). SHAPEIT-IMPUTE2 employing HRC outperformed 1000G (64.50% vs. 59.17%; 1.69% vs. 0.75% for high-quality rare and ultra-rare variants, respectively, Wilcoxon p-value &lt; 0.001). SHAPEIT-IMPUTE2 outperformed MaCH-Admix. Compared to 1000G, HRC-imputation retrieved a higher number of high-quality rare and ultra-rare variants, despite showing lower agreement between imputed and WES variants (e.g., rare: 98.86% for HRC vs. 99.02% for 1000G). High Kappa (K = 0.99) was observed for both reference panels. Twelve G206A mutation carriers were imputed and all validated by confirmation genotyping. African ancestry was associated with higher imputation errors for uncommon and rare variants (p-value &lt; 1e-05).ConclusionReference panels with larger numbers of haplotypes can improve imputation quality for rare and ultra-rare variants in admixed populations such as CH. Ethnic composition is an important predictor of imputation accuracy, with higher African ancestry associated with poorer imputation accuracy

Recommendations for active correction of hypernatremia in volume-resuscitated shock or sepsis patients should be taken with a grain of salt: A systematic review

Background: Healthcare-acquired hypernatremia (serum sodium >145 mEq/dL) is common among critically ill and other hospitalized patients and is usually treated with hypotonic fluid and/or diuretics to correct a “free water deficit.� However, many hypernatremic patients are eu- or hypervolemic, and an evolving body of literature emphasizes the importance of rapidly returning critically ill patients to a neutral fluid balance after resuscitation. Objective: We searched for any randomized- or observational-controlled studies evaluating the impact of active interventions intended to correct hypernatremia to eunatremia on any outcome in volume-resuscitated patients with shock and/or sepsis. Data sources: We performed a systematic literature search with studies identified by searching MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, ClinicalTrials.gov, IndexCatalogue of the Library of the Surgeon General’s Office, DARE (Database of Reviews of Effects), and CINAHL and scanning reference lists of relevant articles with abstracts published in English. Data synthesis: We found no randomized- or observational-controlled trials measuring the impact of active correction of hypernatremia on any outcome in resuscitated patients. Conclusion: Recommendations for active correction of hypernatremia in resuscitated patients with sepsis or shock are unsupported by clinical research acceptable by modern evidence standards.ECU Open Access Publishing Support Fun

Germinoma pineal como causa de panhipopituitarismo: reporte de un caso

Introduction: Intracranial germ cell tumors are rare neoplasms primarily affecting the pediatric population. The clinical presentation varies by location and size. Lesions in the pineal region often cause obstructive hydrocephalus, while lesions in the suprasellar region typically present with hypothalamic-pituitary axis dysfunction. A pineal germ cell tumor presenting with endocrine disturbances is a extremely rare entity. One case of a sixteen-year-old male with panhypopituitarism secondary to a pineal germinoma is reported. Material and methods: This patient was referred to the emergency department after his routine laboratory values showed hypernatremia. He presented with increased thirst, polyuria, and fatigue of one-year duration. Clinical and laboratory evaluation revealed diabetes insipidus, panhypopituitarism, and bitemporal hemianopsia. He received hormone replacement therapy. Three months later, a follow-up magnetic resonance imaging revealed a mass at the pineal region diagnosed as germinoma. Conclusion: After treatment with chemotherapy and radiation, he achieved complete resolution of the lesion. However, there was no marked clinical improvement and he continued to require hormone replacement therapy.Introducción: Los tumores de células germinales intracraneales constituyen un grupo infrecuente de neoplasias que afectan principalmente a la población pediátrica. Su presentación clínica varía en función de la localización y el tamaño del tumor. Las lesiones localizadas en la región pineal a menudo causan hidrocefalia obstructiva, mientras que las lesiones de localización supraselar, usualmente se asocian a disfunción del eje hipotálamo-hipofisario. Un tumor germinal de localización pineal que curse con endocrinopatías es una entidad extremadamente rara. Por tanto, reportamos el caso de un paciente masculino de 16 años de edad, con panhipopituitarismo secundario a un germinoma pineal.  Material y métodos: Este paciente fue referido al Departamento de Emergencias tras presentar hipernatremia en un análisis sanguíneo de rutina. Se presentó con polidipsia, poliuria y fatiga de un año de evolución. Las evaluaciones clínicas y pruebas de laboratorio reportaron diabetes insípida, panhipopituitarismo y hemianopsia bitemporal. El paciente recibió terapia de sustitución hormonal y tres meses después, la resonancia magnética de seguimiento reveló una masa en el área pineal que, a través de una posterior evaluación, fue diagnosticada como germinoma. Conclusión: Luego de tratamiento con quimioterapia y radiación, hubo una resolución completa de la lesión. Sin embargo, no hubo mejoría clínica significativa y el paciente continúo necesitando terapia de reemplazo hormonal