Hypoxia induces transgenerational epigenetic inheritance of small RNAs.

Animals sense and adapt to decreased oxygen availability, but whether and how hypoxia exposure in ancestors can elicit phenotypic consequences in normoxia-reared descendants are unclear. We show that hypoxia educes an intergenerational reduction in lipids and a transgenerational reduction in fertility in the nematode Caenorhabditis elegans. The transmission of these epigenetic phenotypes is dependent on repressive histone-modifying enzymes and the argonaute HRDE-1. Feeding naive C. elegans small RNAs extracted from hypoxia-treated worms is sufficient to induce a fertility defect. Furthermore, the endogenous small interfering RNA F44E5.4/5 is upregulated intergenerationally in response to hypoxia, and soaking naive normoxia-reared C. elegans with F44E5.4/5 double-stranded RNA (dsRNA) is sufficient to induce an intergenerational fertility defect. Finally, we demonstrate that labeled F44E5.4/5 dsRNA is itself transmitted from parents to children. Our results suggest that small RNAs respond to the environment and are sufficient to transmit non-genetic information from parents to their naive children.

Imputing observed blood pressure for antihypertensive treatment: impact on population and genetic analyses.

BACKGROUND: Elevated blood pressure (BP), a heritable risk factor for many age-related disorders, is commonly investigated in population and genetic studies, but antihypertensive use can confound study results. Routine methods to adjust for antihypertensives may not sufficiently account for newer treatment protocols (i.e., combination or multiple drug therapy) found in contemporary cohorts. METHODS: We refined an existing method to impute unmedicated BP in individuals on antihypertensives by incorporating new treatment trends. We assessed BP and antihypertensive use in male twins (n = 1,237) from the Vietnam Era Twin Study of Aging: 36% reported antihypertensive use; 52% of those treated were on multiple drugs. RESULTS: Estimated heritability was 0.43 (95% confidence interval (CI) = 0.20-0.50) and 0.44 (95% CI = 0.22-0.61) for measured systolic BP (SBP) and diastolic BP (DBP), respectively. We imputed BP for antihypertensives by 3 approaches: (i) addition of a fixed value of 10/5mm Hg to measured SBP/DBP; (ii) incremented addition of mm Hg to BP based on number of medications; and (iii) a refined approach adding mm Hg based on antihypertensive drug class and ethnicity. The imputations did not significantly affect estimated heritability of BP. However, use of our most refined imputation method and other methods resulted in significantly increased phenotypic correlations between BP and body mass index, a trait known to be correlated with BP. CONCLUSIONS: This study highlights the potential usefulness of applying a representative adjustment for medication use, such as by considering drug class, ethnicity, and the combination of drugs when assessing the relationship between BP and risk factors.

Untreated hypertension decreases heritability of cognition in late middle age.

Hypertension is a risk factor for cognitive decline, but the mechanisms underlying the effects of hypertension on cognition, particularly in midlife, are unclear. We examined whether hypertension modifies genetic influences on individual differences in cognition. Nine cognitive domains and general cognitive ability were assessed in a sample of 1,237 male twins aged 51-60 who were divided into three blood pressure groups: non-hypertensive; medicated hypertensive; and unmedicated hypertensive. Heritability was significantly lower among unmedicated hypertensives compared to medicated hypertensives and non-hypertensives for visual-spatial ability (p = 0.013) and episodic memory (p = 0.004). There were no heritability differences between non-hypertensives and medicated hypertensives. In addition, there were no significant differences in mean level cognition across the three blood pressure groups. These results suggest that in middle-aged men, untreated hypertension suppresses normal genetic influences on individual differences in certain domains of cognition prior to the emergence of hypertension-related effects on cognitive performance. These results further suggest that antihypertensive medication may protect against or reverse this effect.

A 35-year longitudinal assessment of cognition and midlife depression symptoms: the Vietnam Era Twin Study of Aging.

OBJECTIVE: To determine whether early adult cognitive ability is a risk factor for depressive symptoms in midlife and how genetic and environmental influences explain the association and to examine cross-sectional relationships between depressive symptoms and specific cognitive abilities at midlife. DESIGN: A 35-year longitudinal and cross-sectional twin study of cognitive aging. SETTING: Large multicenter study in the United States. PARTICIPANTS: One thousand two hundred thirty-seven male twins aged 51 to 60 years. MEASUREMENTS: At the age of 20 years and midlife, participants completed the same version of a general cognitive ability test (Armed Forces Qualification Test [AFQT]). Midlife testing included an extensive neurocognitive protocol assessing processing speed, verbal memory, visual-spatial memory, working memory, executive function, and visual-spatial ability. Participants completed the Center for Epidemiologic Studies Depression Scale before cognitive testing and provided health and life style information during a medical history interview. RESULTS: Lower age 20 AFQT scores predicted higher levels of depressive symptoms at age 55 years (r = -0.16,p <0.001). In bivariate twin modeling, 77% of the correlation between early cognitive ability and midlife depressive symptoms was due to shared genetic influences. Controlling for current age, age 20 AFQT, and nonindependence ofobservations, depressive symptoms were associated with worse midlife AFQT scores and poorer performance in all cognitive domains except verbal memory. CONCLUSION: Results suggest that low cognitive ability is a risk factor for depressive symptoms; this association is partly due to shared genetic influences. Crosssectional analyses indicate that the association between depressive symptoms and performance is not linked to specific cognitive domains.

When help becomes a hindrance: mental health referral systems as barriers to care for primary care physicians treating patients with Alzheimer's disease.

OBJECTIVES: To describe structural barriers to mental health specialists and consequences of these barriers to care for patients with dementia and neuropsychological symptoms and their primary care physicians (PCPs). DESIGN: Cross-sectional qualitative interview study of PCPs. SETTING: Physicians' offices, primarily managed care. PARTICIPANTS: Forty PCPs in Northern California. MEASUREMENTS: Open-ended interviews lasted 30-60 minutes. The interview guide covered clinician background, practice setting, clinical care of a particular patient, and general approach to managing patients with Alzheimer disease or related dementias.Interviews were transcribed and themes reflecting referrals identified. RESULTS: Ninety-three percentage of the PCPs described problematic access to and communication with mental health specialists (in particular psychiatrists and neuropsychologists) as impediments to effective care for dementia patients. Thematic analysis identified structural barriers to mental health referrals ranging from problems with managed care and reimbursement policies to lack of trained providers and poor geographic distribution of specialists. Structural barriers compromised care for patients with dementia because the barriers limited PCP treatment options, and resources, impacted office staff and time with other patients, impeded and delayed care, and fostered poor communication and lack of coordinated care. Negative consequences for PCPs included increased frustration,conflict, and burnout. CONCLUSION: PCPs viewed problems created by onerous referral systems, such as mental health carve outs, as particularly burdensome for elderly patients with comorbid dementia and neuropsychiatric problems. These problems were cited by PCPs across different types of practice settings. PCPs managed treatment of neurobehavioral symptoms as best they could despite lack of specialist support.

A new brief instrument for assessing decisional capacity for clinical research.

CONTEXT: There is a critical need for practical measures for screening and documenting decisional capacity in people participating in different types of clinical research. However, there are few reliable and validated brief tools that could be used routinely to evaluate individuals' capacity to consent to a research protocol. OBJECTIVE: To describe the development, testing, and proposed use of a new practical instrument to assess decision-making capacity: the University of California, San Diego Brief Assessment of Capacity to Consent (UBACC). The UBACC is intended to help investigators identify research participants who warrant more thorough decisional capacity assessment and/or remediation efforts prior to enrollment. DESIGN, SETTING, AND PARTICIPANTS: We developed the UBACC as a 10-item scale that included questions focusing on understanding and appreciation of the information concerning a research protocol. It was developed and tested among middle-aged and older outpatients with schizophrenia and healthy comparison subjects participating in research on informed consent. In an investigation of reliability and validity, we studied 127 outpatients with schizophrenia or schizoaffective disorder and 30 healthy comparison subjects who received information about a simulated clinical drug trial. Internal consistency, interrater reliability, and concurrent (criterion) validity (including correlations with an established instrument as well as sensitivity and specificity relative to 2 potential "gold standard" criteria) were measured. MAIN OUTCOME MEASURES: Reliability and validity of the UBACC. RESULTS: The UBACC was found to have good internal consistency, interrater reliability, concurrent validity, high sensitivity, and acceptable specificity. It typically took less than 5 minutes to administer, was easy to use and reliably score, and could be used to identify subjects with questionable capacity to consent to the specific research project. CONCLUSION: The UBACC is a potentially useful instrument for screening large numbers of subjects to identify those needing more comprehensive decisional capacity assessment and/or remediation efforts.

Anxiety disorders in a public mental health system: clinical characteristics and service use patterns.

BACKGROUND: Anxiety disorders are among the most common forms of psychiatric disorder, yet few investigations have examined the prevalence or service use of clients with anxiety disorders in the public mental health sector. METHODS: We examined demographics, clinical information, and service use in clients with anxiety disorders enrolled in San Diego County Adult and Older Adult Mental Health Services in fiscal 2002-2003. RESULTS: Almost 15% of the sample had a diagnosis of an anxiety disorder based on administrative billing data. Most anxiety disorder clients had additional psychiatric diagnoses, most commonly depression. Clients with both anxiety disorders and depression were more likely than those with anxiety or depression alone to use emergency psychiatric services and outpatient services than those with depression alone. Those with anxiety disorders alone used more outpatient services than those with depression alone. LIMITATION: Data were taken from an administrative database. CONCLUSIONS: Data indicate that anxiety disorders are not uncommon in public mental health settings and are associated with higher utilization of outpatient mental health services.

Psychiatric symptom dimensions among asian americans and native hawaiians: An analysis of the symptom checklist.

Standardized instruments are often used to assess the need for mental health services in a community. Such instruments are usually standardized on Caucasian samples and are generally assumed to be appropriate for different ethnocultural minorities. However, this assumption may be in error because cultural groups vary in their expression, manifestation, and reporting of symptoms. This article analyzes the responses to a standardized instrument, the Symptom Checklist (SCL), for four ethnic groups in Hawai'i: Caucasians, Filipinos, Japanese, and Native Hawaiians. Factor analysis using a procrustes rotation was used to force the data to fit into the five hypothesized factors of the SCL (somatization, obsessive-compulsive, interpersonal sensitivity, depression, and anxiety). It showed that the scale item loadings generally did not correspond to the hypothesized factors. Among the ethnic groups, Caucasians appeared to have the best fit between the empirical and hypothesized factors whereas Native Hawaiians had the worst fit. Our results reinforce the importance of assessing established psychiatric symptom scales prior to their use on different ethnocultural minorities.