Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer’s disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson’s disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
Alzheimer’s disease; amyloid-β protein precursor; genetics; human; MAPT protein; PSEN1 protein; PSEN2 protein
Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
Eleven susceptibility loci for late-onset Alzheimer’s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer’s disease cases and 37,154 controls. In stage 2,11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer’s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer’s disease.
To evaluate if there are racial differences between African-American and Caucasian women who have hysterectomy for benign conditions in terms of (1) presenting symptoms (prolapse, vaginal bleeding, pain, and known history of leiomyomas), (2) serum estradiol and testosterone levels at the visit before hysterectomy, and (3) uterine weight.
A multi-ethnic, multisite, community-based longitudinal cohort study of 3,302 women ages 42–52 at enrollment was conducted. During 9 years of follow-up, 203 African-American and Caucasian women reported a hysterectomy, 90 with evidence of uterine leiomyomas. Women were surveyed regarding their overall perceived health before and after hysterectomy, presenting symptoms, and their motivations for surgery. Serum estradiol and testosterone levels were measured. Uterine weight at time of hysterectomy and clinical pathology were determined via medical record abstraction.
Previously diagnosed leiomyomas were presenting symptoms more frequently in African-American women than Caucasian women (85% vs. 63%; p = .02). African-American women had less prolapse than Caucasian women (0% vs. 10%; p = 0.04). Chronic pain was a more frequent reason for hysterectomy in African-American women than in Caucasian women (49% vs. 29%; p = .05). There were no differences between the groups in levels of estradiol or testosterone. African-American women had almost twice the uterine weight as that of Caucasian women (448 vs. 240 g; p = .0005).
Racial differences in frequency of hysterectomy for benign conditions are consistent with differences in presenting symptoms, where African-American women seemingly have larger, more symptomatic fibroids.
Members of the CD28 family play important roles in regulating T cell functions and share a common gene structure profile. We have identified VSTM3 as a protein whose gene structure matches that of the other CD28 family members. This protein (also known as TIGIT and WUCAM) has been previously shown to affect immune responses and is expressed on NK cells, activated and memory T cells, and regulatory T cells. The nectin-family proteins CD155 and CD112 serve as counter-structures for VSTM3 and CD155 and CD112 also bind to the activating receptor CD226 on T cells and NK cells. Hence, this group of interacting proteins forms a network of molecules similar to the well-characterized CD28-CTLA4-CD80-CD86 network. In the same way that soluble CTLA4 can be used to block T cell responses, we show that soluble Vstm3 attenuates T cell responses in vitro and in vivo. Moreover, animals deficient in Vstm3 are more sensitive to autoimmune challenges indicating that this new member of the CD28 family is an important regulator of T cell responses.
The purpose of this study was to provide estimates for the prevalence of reproductive cancer risk factors among Alaska Native (AN) women who enrolled in the Alaska Education and Research Towards Health (EARTH) Study from 2004 to 2006.
A total of 2,315 AN women 18 years or older completed reproductive health questions as part of a comprehensive health history questionnaire. The reproductive health section included menstrual status (age at menarche and menopause), pregnancy and live birth history, use of hormonal contraception, hormone replacement therapy, and history of hysterectomy and/or oophorectomy.
A total of 463 (20%) of women experienced menarche before age 12 with a decline in mean age at menarche by age cohort. More than 86% had been pregnant (mean number of pregnancies, 3.8; mean number of live births, 2.9). More than one half of women (58%) had their first live birth between the ages of 18 and 24. Almost 28% of participants had completed menopause, of whom 24% completed menopause after age 52. Fewer than half (43%) reported ever using hormone replacement therapy. Almost two thirds (62%) reported ever using oral contraceptives, and fewer reported ever using birth control shots (30%) or implants (10%).
This study is unique in reporting reproductive health factors among a large group of AN women. These data show that AN women have selective protective factors for reproductive cancers, including low nulliparity rates, low use of menopausal estrogens, and common use of contraceptive hormones. However, analysis by age cohorts indicates decreasing age at menarche that might increase the risk for reproductive cancers among AN women in the future.
Psychotic symptoms occur in approximately 40% of subjects with Alzheimer’s disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWAS) to identify loci that a) increase susceptibility to an AD and subsequent psychotic symptoms; or b) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from GERAD1, the NIA-LOAD family study and the University of Pittsburgh ADRC GWAS. Unobserved genotypes were imputed to provide data on > 1.8 million SNPs. Analyses in each dataset were completed comparing a) AD+P to AD-P cases, and b) AD+P cases with controls (GERAD1, ADRC only). Aside from the APOE locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; ‘AD+PvAD-P’ P=2.85 × 10−7; ‘AD+PvControls’ P=1.11 × 10−4). SNPs upstream of SLC2A9 (rs6834555, P=3.0×10−7) and within VSNL1 (rs4038131, P=5.9×10−7) showed strongest evidence for association with AD+P when compared to controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterised.
Alzheimer’s disease; psychosis; behavioural symptoms; genome-wide association study; genetic
Between 1995 and 1998, tribally owned Southcentral Foundation (SCF) incrementally assumed responsibility from the Indian Health Service (IHS) for primary care services on the Alaska Native Medical Center (ANMC) campus in Anchorage, Alaska. In 1999, SCF began implementing components of a Patient-Centered Medical Home (PCMH) model to improve access and continuity of care.
To evaluate hospitalisation trends before, during and after PCMH implementation.
Time series analysis of aggregated medical record data.
Regression analysis with correlated errors was used to estimate trends over time for the percent of customer-owners hospitalised overall and for specific conditions during 4 time periods (March 1996–July 1999: SCF assumes responsibility for primary care; August 1999–July 2000: PCMH implementation starts; August 2000–April 2005: early post-PCMH implementation; May 2005–December 2009: later post-PCMH implementation). Analysis was restricted to individuals residing in Southcentral Alaska and receiving health care at ANMC.
The percent of SCF customer-owners hospitalised per month for any reason was steady before and during PCMH implementation, declined steadily immediately following implementation and subsequently stabilised. The percent hospitalised per month for unintentional injury or poisoning also declined during and after the PCMH implementation. Among adult asthma patients, the percent hospitalised annually for asthma declined prior to and during implementation and remained lower thereafter. The percent of heart failure patients hospitalised annually for heart failure remained relatively constant throughout the study period while the percent of hypertension patients hospitalised for hypertension shifted higher between 1999 and 2002 compared to earlier and later years.
Implementation of PCMH at SCF was accompanied by decreases in the percent of customer-owners hospitalised monthly for any reason and for unintentional injury and in the percent of asthma patients hospitalised annually for asthma. Increased accessibility to empanelled care teams may have contributed to decreased need for hospitalisation.
Patient-Centered Medical Home; Alaska Native; asthma; inpatient hospitalization; time series analysis
This report describes the results of a study to determine whether a community-based sentinel surveillance system can be developed and implemented to assess the health effects of climate change, and to contribute to local discussions to mitigate these health effects. The purpose of this report is to describe the process and outcomes of this innovative approach to identifying priority areas for adaptation investment. This report can be used to assist local, state and federal governments in determining how to develop actions and policies to promote adaptation to climate change.
To evaluate the health effects of climate change in rural Alaska.
We conducted an iterative and participatory process to develop metrics, an instrument and a protocol to collect sentinel surveillance data on the health effects of climate change in 3 ecologically distinct regions of the state.
We collected surveillance data from 91 study participants over the course of 12 months. These data were analyzed and categorized by frequency and association between specific health outcomes or health-related factors (such as food security) and reported exposure to environmental effects of climate change. We found significant associations between several health outcomes and health outcome mediators and reported exposures. We presented these data to study participants in community settings and moderated discussions of likely causal factors for these measured associations, and helped community residents to identify specific adaption measures to mitigate those health effects.
We conclude that community-based sentinel surveillance is an effective method for assessing health outcomes from exposure to environmental effects of climate change, and informing climate change health adaptation planning in Alaskan communities. We contend that it would be effective in other regions of the nation as well.
community-based; surveillance; adaptation; climate change; Alaska
Psychotic symptoms occur in approximately 40% of subjects with Alzheimer’s disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWAS) to identify loci that a) increase susceptibility to an AD and subsequent psychotic symptoms; or b) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD−P) and 5659 controls were drawn from GERAD1, the NIA-LOAD family study and the University of Pittsburgh ADRC GWAS. Unobserved genotypes were imputed to provide data on > 1.8 million SNPs. Analyses in each dataset were completed comparing a) AD+P to AD−P cases, and b) AD+P cases with controls (GERAD1, ADRC only). Aside from the APOE locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; ‘AD+PvAD−P’ P=2.85 × 10−7; ‘AD+PvControls’ P=1.11 × 10−4). SNPs upstream of SLC2A9 (rs6834555, P=3.0×10−7) and within VSNL1 (rs4038131, P=5.9×10−7) showed strongest evidence for association with AD+P when compared to controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterised.
Alzheimer’s disease; psychosis; behavioural symptoms; genome-wide association study; genetic
Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain.
We tested 138 mtDNA variants for association with AD in a powerful sample of 4,133 AD case patients and 1,602 matched controls from 3 Caucasian populations. Of the total population, 3,250 case patients and 1,221 elderly controls met the quality control criteria and were included in the analysis.
In the largest study to date, we failed to replicate the published findings. Meta-analysis of the available data showed no evidence of an association with AD.
The current evidence linking common mtDNA variations with AD is not compelling.
The purpose of this study was to determine the longitudinal association between menopausal vasomotor symptoms (VMS) and urinary N-telopeptide level (NTX) according to menopausal stage. We analyzed data from 2283 participants of the Study of Women's Health Across the Nation, a longitudinal community-based cohort study of women aged 42 to 52 years at baseline. At baseline and annually through follow-up visit 8, participants provided questionnaire data, urine samples, serum samples, and anthropometric measurements. Using multivariable repeated-measures mixed models, we examined associations between annually assessed VMS frequency and annual NTX measurements. Our results show that mean adjusted NTX was 1.94 nM of bone collagen equivalents (BCE)/mM of creatinine higher among early perimenopausal women with any VMS than among early perimenopausal women with no VMS (p < .0001). Mean adjusted NTX was 2.44 nM BCE/mM of creatinine higher among late perimenopausal women with any VMS than among late perimenopausal women with no VMS (p = .03). Among premenopausal women, VMS frequency was not significantly associated with NTX level. When NTX values among women with frequent VMS (≥6 days in past 2 weeks) were expressed as percentages of NTX values among women without frequent VMS, the differences were 3% for premenopausal women, 9% for early perimenopausal women, 7% for late perimenopausal women, and 4% for postmenopausal women. Adjustment for serum follicle-stimulating hormone (FSH) level greatly reduced the magnitudes of associations between VMS and NTX level. We conclude that among early perimenopausal and late perimenopausal women, those with VMS had higher bone turnover than those without VMS. Prior to the final menstrual period, VMS may be a marker for risk of adverse bone health. © 2011 American Society for Bone and Mineral Research.
HOT FLASHES; VASOMOTOR SYMPTOMS; BONE TURNOVER; URINARY N-TELOPEPTIDE; NTX
Neprilysin (NEP), also known as membrane metalloendopeptidase (MME), is considered amongst the most important β-amyloid (Aβ)-degrading enzymes with regard to prevention of Alzheimer’s disease (AD) pathology. Variation in the NEP gene (MME) has been suggested as a risk factor for AD. We conducted a genetic association study of 7MME SNPs – rs1836914, rs989692, rs9827586, rs6797911, rs61760379, rs3736187, rs701109 - with respect to AD risk in a cohort of 1057 probable and confirmed AD cases and 424 age-matched non-demented controls from the United Kingdom, Italy and Sweden. We also examined the association of these MME SNPs with NEP protein level and enzyme activity, and on biochemical measures of Aβ accumulation in frontal cortex – levels of total soluble Aβ, oligomeric Aβ1-42, and guanidine-extractable (insoluble) Aβ – in a sub-group of AD and control cases with post-mortem brain tissue. On multivariate logistic regression analysis one of the MME variants (rs6797911) was associated with AD risk (P = 0.00052, Odds Ratio (O.R. = 1.40, 95% confidence interval (1.16-1.70)). None of the SNPs had any association with Aβ levels; however, rs9827586 was significantly associated with NEP protein level (p=0.014) and enzyme activity (p=0.006). Association was also found between rs701109 and NEP protein level (p=0.026) and a marginally non-significant association was found for rs989692 (p=0.055). These data suggest that MME variation may be associated with AD risk but we have not found evidence that this is mediated through modification of NEP protein level or activity.
Neprilysin; MME; gene; association; β-Amyloid; alzheimer disease; polymorphism
Historically, Alaska Native (AN) people have exhibited low overall rates of heart disease mortality compared with the U.S. white (USW) population. We compared AN and USW heart disease mortality rates during the 27-year period from 1981 through 2007.
We compared AN and USW heart disease mortality rates overall and by gender, age, and disease subtype. We calculated age-adjusted rates for AN people for three nine-year periods from 1981 through 2007 and compared them with the rates for USW people.
AN people ≥35 years of age had a significantly lower rate of heart disease mortality compared with their USW counterparts (rate ratio [RR] = 0.80). The lower overall RR was due primarily to a lower ischemic heart disease mortality RR (RR=0.63). Overall heart disease mortality decreased during the 27-year study period for both the AN (33.1%) and USW (35.0%) populations. However, hypertensive heart disease mortality increased 155.2% for AN people and 13.7% for USW people. Age-specific heart disease mortality was about 30.0% lower for AN people ≥75 years of age compared with their USW counterparts, while it was virtually identical for the two racial/ethnic groups among people 35–74 years of age.
The age-adjusted AN heart disease mortality rate was consistently about 20.0% lower than the USW rate from 1981 through 2007, with similar RRs for men and women. However, combining all ages and all heart disease subgroups into a single, age-adjusted statistic obscures many important differences across ages and disease subtypes.
The effect of change in reproductive hormones and menopause on incident obesity (body mass index ≥30 kg/m2) and severe obesity (body mass index ≥35 kg/m2) was evaluated over 9 years in 3,260 US women recruited in the multiethnic Study of Women's Health Across the Nation in 1996–1997. After 9 years, cumulative incidences of obesity and severe obesity reached 21.8% and 12.3%, respectively. In multivariate analysis, hormone changes, chronic health conditions, lower physical activity, race/ethnicity, and age were significantly associated with incident obesity and/or severe obesity. The odds of incident severe obesity increased with surgical menopause (odds ratio (OR) = 5.07, 95% confidence interval (CI): 2.29, 11.20; P < 0.001) and initiation of hormone therapy prior to 12 months of amenorrhea (OR = 2.94, 95% CI: 1.14, 7.58; P = 0.03). Predictors of obesity included an increase in free androgen index (OR = 1.37, 95% CI: 1.12, 1.68; P = 0.002) and a decrease in sex hormone-binding globulin (OR = 0.60, 95% CI: 0.45, 0.80; P = 0.0005). Similar results were found for severe obesity. Obesity rates varied by race, but no hormone-by-race interactions were observed. These longitudinal data demonstrate that higher androgens, lower sex hormone-binding globulin, surgical menopause, and early hormone therapy use predict incident obesity and/or severe obesity in a multiracial cohort of women transitioning into menopause.
hormones; menopause; obesity; reproduction
Genetic variation of the α-synuclein gene (SNCA) is known to cause familial parkinsonism, however the role of SNCA variants in sporadic Parkinson’s disease (PD) remains elusive. The present study identifies an association of common SNCA polymorphisms with disease susceptibility in a series of Irish PD patients. There is evidence for association with alternate regions, of protection and risk which may act independently/synergistically, within the promoter region (Rep1; OR: 0.59, 95% CI: 0.37 – 0.84) and the 3′UTR of the gene (rs356165; OR: 1.67, 95% CI: 1.08 – 2.58). Given previous reports of association a collaborative effort is required which may exploit global linkage disequilibrium patterns for SNCA and standardise polymorphic markers used in each population. It is now crucial to identify the susceptibility allele and elucidate its functionality which may generate a therapeutic target for PD.
α-Synuclein; polymorphism; Parkinson’s disease
The Alaska Education and Research Towards Health (EARTH) Study is being conducted to determine the prevalence of clinically measured chronic disease risk factors in a large population of American Indian/Alaska Native people (AI/AN). We report these estimates and compare them with those for the overall US population, as assessed by the National Health and Nutrition Examination Survey (NHANES).
We measured blood pressure, height, weight, and fasting serum lipids and glucose in a prospective cohort of 3,822 AI/AN participants who resided in Alaska during 2004 through 2006. We categorized participants as having chronic disease risk factors if their measurements exceeded cutoffs that were determined on the basis of national recommendations. We analyzed the prevalence of risk factors by sex and age and compared the age-adjusted prevalence with 1999-2004 NHANES measurements.
EARTH participants were significantly more likely than NHANES participants to be overweight or obese and to have impaired fasting glucose, low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol, and hypertension. The prevalence of high total cholesterol and triglycerides was not significantly different between the 2 study populations.
We provide baseline clinical measurements for chronic disease risk factors for a larger study sample than any previous study of AI/AN living in Alaska. The prevalence of most risk factors measured exceeded national rates. These data can be used to tailor health interventions and reduce health disparities.
As associations between endogenous sex hormones and the vasculature are not well characterized, the objective was to examine the cross-sectional associations of menopausal status and endogenous sex hormones with vascular characteristics.
Common carotid artery adventitial diameter and intima-media thickness were determined using B-mode ultrasound among 483 middle-aged women enrolled in the Pittsburgh and Chicago sites of the Study of Women’s Health Across the Nation.
Sixty-two percent of women were pre- or early perimenopausal (<3 months amenorrhea), 12% were late perimenopausal (3-12 months amenhorrhea), and 27% were postmenopausal (≥12 months amenorrhea). After adjustment for age, compared to pre-/early perimenopause, late perimenopause was associated with a 0.28 mm larger adventitial diameter (p=0.001), while postmenopause was associated with a 0.15 mm larger adventitial diameter (p=0.040). Adjustment for traditional cardiovascular risk factors slightly attenuated these associations, but the association with late perimenopause remained statistically significant (p=0.001). Each standard deviation lower log estradiol value was associated with a 0.07 mm larger adventitial diameter after adjustment for traditional cardiovascular risk factors (p=0.023), while other endogenous hormones showed no associations. Intima-media thickness values were not significantly associated with menopausal status or endogenous sex hormones after adjustment for age.
The menopausal transition and declining estrogen levels are associated with alterations of the peripheral vasculature, which may help to explain the increased risk of cardiovascular disease with postmenopause.
estradiol; endogenous sex hormones; menopause; arteriosclerosis
To determine whether women with vasomotor symptoms (VMS) have lower bone mineral density (BMD) than women without VMS.
We analyzed data from baseline to annual follow-up visit 5 for 2213 participants in the bone substudy of the Study of Women’s Health Across the Nation. At baseline, women were aged 42 to 52 years, had intact uterus and ≥1 ovary, were not using exogenous hormones, were not pregnant or lactating, and were pre- or early perimenopausal. Menopausal stage and VMS were assessed by annual questionnaire. Menopausal stages were premenopausal, early perimenopausal, late perimenopausal, and postmenopausal. Using repeated measures mixed models, we determined the association between VMS (any vs. none) and BMD (by dual x-ray absorptiometry) within each menopause status category.
After controlling for age, time within each menopausal stage, race/ethnicity, study site, and baseline menopause stage, postmenopausal women with any VMS had lower lumbar (0.008g/cm2 lower, P=0.001) and lower total hip (0.005 g/cm2 lower, P=0.04) BMD than postmenopausal women without VMS. Compared to early perimenopausal women without VMS, early perimenopausal women with any VMS had lower femoral neck BMD (0.003g/cm2 lower, P=0.0001). Premenopausal women with any VMS had lower femoral neck BMD (0.003g/cm2 lower, P=0.03), compared to premenopausal women without VMS.
Even in the earliest menopause transition stages, women with VMS had lower BMD than women without VMS. Effects varied by anatomical site, being most evident in postmenopausal women at the lumbar spine and total hip, and among premenopausal and early perimenopausal women at the femoral neck.
Menopause; hot flashes; vasomotor symptoms; bone mineral density
Our study evaluates the symptoms commonly attributed to adenomyosis in women undergoing the menopausal transition. We hypothesized that adenomyosis is more commonly seen in women with fibroids, pelvic pain, abnormal uterine bleeding, and in the presence of endometriosis.
multi-site community based study
SWAN study enrollees who had hysterectomies
Main Outcome Measurements
Relationship of Adenomyosis to other entities
Adenomyosis was found in 48% of 137 patients. Frequencies of presenting symptoms were similar in those with and without evidence of adenomyosis. The same prevalence of fibroids, 37 % versus 43% (p=0.39), endometriosis, 3% versus 5% (p=0.41), abnormal bleeding, 27% versus 33% (p=0.72), or chronic pelvic pain in the presence of fibroids 12% versus 17%, (p=0.58), was seen in the presence or absence of adenomyosis.
Adenomyosis is a common diagnosis seen in hysterectomized specimens from women undergoing the perimenopausal transition. Adenomyosis is equally common in women who also have fibroids, endometriosis, pelvic pain, or abnormal uterine bleeding, and those women that do not. Therefore, adenomyosis is an incidental finding, not the source of the symptomatology. It appears not to be a “disease” per se, but a normal variant.
Adenomyosis; Endometriosis; Fibroids; Pelvic Pain
ZnT3 is a membrane Zn2+ transporter that is responsible for concentrating Zn2+ into neuronal presynaptic vesicles. Zn2+ homeostasis in the brain is relevant to Alzheimer's disease (AD) because Zn2+ released during neurotransmission may bind to Aβ peptides, accelerating the assembly of Aβ into oligomers which have been shown to impair synaptic function.
We quantified ZnT3 mRNA levels in Braak-staged human post mortem (pm) brain tissue from medial temporal gyrus, superior occipital gyrus, superior parietal gyrus, superior frontal gyrus and cerebellum from individuals with AD (n = 28), and matched controls (n = 5) using quantitative real-time PCR. ZnT3 mRNA levels were significantly decreased in all four cortical regions examined in the AD patients, to 45-60% of control levels. This reduction was already apparent at Braak stage 4 in most cortical regions examined. Quantification of neuronal and glial-specific markers in the same samples (neuron-specific enolase, NSE; and glial fibrillary acidic protein, GFAP) indicated that loss of cortical ZnT3 expression was more pronounced, and occurred prior to, significant loss of NSE expression in the tissue. Significant increases in cortical GFAP expression were apparent as the disease progressed. No gene expression changes were observed in the cerebellum, which is relatively spared of AD neuropathology.
This first study to quantify ZnT3 mRNA levels in human pm brain tissue from individuals with AD and controls has revealed a significant loss of ZnT3 expression in cortical regions, suggesting that neuronal cells in particular show reduced expression of ZnT3 mRNA in the disease. This suggests that altered neuronal Zn2+ handling may be an early event in AD pathogenesis.
Many epidemiologic studies include symptom checklists assessing recall of symptoms over a specified time period. Little research exists regarding the congruence of short-term symptom recall with daily self-reporting. The authors assessed the sensitivity and specificity of retrospective reporting of vasomotor symptoms using data from 567 participants in the Study of Women's Health Across the Nation (1997–2002). Daily assessments were considered the “gold standard” for comparison with retrospective vasomotor symptom reporting. Logistic regression was used to identify predictors of sensitivity and specificity for retrospective reporting of any vasomotor symptoms versus none in the past 2 weeks. Sensitivity and specificity were relatively constant over a 3-year period. Sensitivity ranged from 78% to 84% and specificity from 85% to 89%. Sensitivity was lower among women with fewer symptomatic days in the daily assessments and higher among women reporting vasomotor symptoms in the daily assessment on the day of retrospective reporting. Specificity was negatively associated with general symptom awareness and past smoking and was positively associated with routine physical activity and Japanese ethnicity. Because many investigators rely on symptom recall, it is important to evaluate reporting accuracy, which was relatively high for vasomotor symptoms in this study. The approach presented here would be useful for examining other symptoms or behaviors.
data collection; hot flashes; mental recall; sensitivity and specificity; sweating; vasomotor system
Physical functioning measures are considered integrated markers of the aging process. This prospective investigation examined relationships between dietary intake of women at midlife in 1996/7 and prevalence of physical functioning limitations four years later, defined by the Medical Outcomes Study SF-36. The sample included 2160 multiethnic women, aged 42–52, from six geographic areas participating in the Study of Women’s Health Across the Nation (SWAN). Associations between measures of diet quality and number of fruit and vegetable servings and prevalent physical functional limitations (no, moderate, or substantial limitations) were tested using logistic regression. The prevalence of moderate and substantial functional limitations was 31% and 10%, respectively. Women in the highest quartile of cholesterol intake had 40% greater odds (OR: 1.4; 95% confidence interval: 1.1, 1.8) of being more limited versus those in the lowest quartile. Women in the highest quartile of fat and saturated fat intake were 50% and 60% more likely to be more limited (OR: 1.5 and 1.6, respectively; 95 % confidence intervals: 1.2, 2.0 and 1.2, 2.1, respectively) versus those in the lowest quartiles. Lower fruit, vegetable and fiber intakes were related to reporting greater functional limitations. Modifying dietary practices could be important in minimizing physical limitations.
diet; disabled persons; body mass index; nutrition
Studies of gene expression in post mortem human brain can contribute to understanding of the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Quantitative real-time PCR (RT qPCR) is often used to analyse gene expression. The validity of results obtained using RT qPCR is reliant on accurate data normalization. Reference genes are generally used to normalize RT qPCR data. Given that expression of some commonly used reference genes is altered in certain conditions, this study aimed to establish which reference genes were stably expressed in post mortem brain tissue from individuals with AD, PD or DLB.
The present study investigated the expression stability of 8 candidate reference genes, (ubiquitin C [UBC], tyrosine-3-monooxygenase [YWHAZ], RNA polymerase II polypeptide [RP II], hydroxymethylbilane synthase [HMBS], TATA box binding protein [TBP], β-2-microglobulin [B2M], glyceraldehyde-3-phosphate dehydrogenase [GAPDH], and succinate dehydrogenase complex-subunit A, [SDHA]) in cerebellum and medial temporal gyrus of 6 AD, 6 PD, 6 DLB subjects, along with 5 matched controls using RT qPCR (TaqMan® Gene Expression Assays). Gene expression stability was analysed using geNorm to rank the candidate genes in order of decreasing stability in each disease group. The optimal number of genes recommended for accurate data normalization in each disease state was determined by pairwise variation analysis.
This study identified validated sets of mRNAs which would be appropriate for the normalization of RT qPCR data when studying gene expression in brain tissue of AD, PD, DLB and control subjects.