The Neurosteroid Allopregnanolone Is Reduced in Prefrontal Cortex in Alzheimer’s Disease

BACKGROUND: Few data are currently available investigating neurosteroids (NS) in Alzheimer's disease (AD). The NS allopregnanolone may be decreased in serum and plasma in patients with AD, but it is unclear if allopregnanolone is also reduced in brain. Because a number of NS exhibit neuroprotective effects and impact cognitive performance in rodent models, these molecules may be relevant to the pathophysiology of neurodegenerative disorders. We therefore investigated prefrontal cortex (PFC) NS levels in AD. METHODS: Neurosteroid levels (allopregnanolone, pregnenolone, dehydroepiandrosterone [DHEA]) were determined in postmortem PFC in 14 male subjects with AD and 15 cognitively intact male control subjects by gas chromatography/mass spectrometry preceded by high-performance liquid chromatography purification. RESULTS: Subjects with AD exhibit significant reductions in allopregnanolone compared with cognitively intact control subjects (median levels = 2.50 ng/g vs. 5.59 ng/g, respectively; p = .02). Allopregnanolone levels are inversely correlated with neuropathological disease stage (Braak), r = -.49, p = .007. Median DHEA levels are elevated in subjects with AD (p = .01). CONCLUSIONS: Subjects with AD demonstrate significant reductions in PFC allopregnanolone levels, a finding that may be relevant to neuropathological disease stage severity. Neurosteroids may have utility as candidate biomarkers in AD.     

Sociodemographic characteristics of the neighborhood and depressive symptoms in older adults: using multilevel modeling in geriatric psychiatry.

OBJECTIVE: Neighborhood sociodemographic characteristics may be important to the mental health of older adults who have decreased mobility and fewer resources. Our objective was to examine the association between neighborhood context and level of depressive symptomatology in older adults in a diverse geographic region of central North Carolina. METHODS: The sample included 2,998 adults 65 or older residing in 91 census tracts. Depressive symptoms were measured using the Center for Epidemiologic Studies-Depression scale (CES-D). Neighborhoods were characterized by five census-based characteristics: socioeconomic disadvantage, socioeconomic advantage, racial/ethnic heterogeneity, residential stability, and age structure. RESULTS: In ecologic level analyses, level of census tract socioeconomic disadvantage was associated with increased depressive symptoms. To determine whether neighborhood context was associated with depressive symptoms independently of individual characteristics, the authors used multilevel modeling. The authors examined the ability of each of five neighborhood (level 2) characteristics to predict a level 1 outcome (CES-D symptoms) controlling for the effects of individual (level 1) characteristics. Younger age, being widowed, lower income, and having some functional limitations were associated with increased depression symptoms conditional on census tract random effects. However, none of the neighborhood characteristics was significantly associated with depression symptoms, conditional on census tract random effects, either unadjusted or adjusted for individual characteristics. CONCLUSION: Any observed association between neighborhood sociodemographic characteristics and individual depressive symptoms in our sample may reflect the characteristics of the individuals who reside in the neighborhood rather than the neighborhood characteristics themselves. The use of multilevel modeling is important to separate these effects.     

Premenstrual symptoms in black and white community samples

Premenstrual syndrome specialty clinics are reported to be almost exclusively attended by white women. This racial discrepancy has raised the question of whether there is a lower prevalence or severity of symptoms during the premenstruum among black women. The authors evaluated selected premenstrual symptoms in a representative community-based sample and found no difference in the prevalence or severity of premenstrual symptoms reported by black and white women, except for a higher prevalence of food cravings among blacks. Exploration of broader sociocultural factors may explain the observed racial difference in seeking help for premenstrual complaints.     

Self-rated depressive symptoms in medical inpatients: age and racial differences.

One thousand and eleven men under age forty (n = 161) or over age sixty-four (n = 850) admitted to medical and neurological services of an acute care hospital were screened for depressive symptoms as part of the Durham VA Mental Health Survey. Thirty-three percent of younger and 22 percent of older men scored 11 or higher on the Geriatric Depression Scale. Self-rated symptoms were most prevalent among younger whites (40%) and least common in older blacks (19%). Other exogenous factors such as being retired or unemployment and prior psychiatric history were also related to depressive symptoms, as were poor functional status, impaired cognitive status, and respiratory illness. Coping resources associated with fewer symptoms were social support and moderate alcohol use. In a subgroup of 443 patients, self-rated symptoms were compared with observer-rated symptoms. Agreement was highest among young Whites and lowest in older Blacks. Other correlates also varied depending on whether self-rated or observer-rated symptoms were considered. We conclude that self-rated symptoms are common among medical inpatients, are linked with and confounded by certain health and sociodemographic factors, and may be relatively insensitive as a measure of depression in elderly blacks.     

Insomnia and heart disease: a review of epidemiologic studies

Since the discovery and successful treatment of sleep apnea, researchers seem to believe that the association between sleep disturbance and coronary heart disease (CHD) has been explained. To determine whether subjective nighttime sleep complaints (trouble sleeping, trouble falling asleep, trouble staying asleep), exclusive of apnea, predicted myocardial infarction and other coronary events, a MEDLINE search was conducted for articles published between January 1976 through August 1997. Ten studies with an explicit measure of association between an insomniac complaint and CHD were identified. Reported risk ratios for various sleep complaints and CHD events ranged from 1.0 for waking too early and CHD death in an elderly North Carolina community to 8.0 for the highest versus lowest quintile of a sleep scale in Finnish men. Higher quality studies showed risk ratios of 1.47-3.90 between trouble falling asleep and coronary events after adjusting for age and various coronary risk factors (combined effect=1.7, p<0.0001). While alternative explanations such as medication use still need to be ruled out, we theorize that a subjective insomniac complaint either may be part of a larger syndrome that includes poor health and depression, or it may be related to continual stressors, reduced slow-wave sleep, and autonomic dysfunction, which increase the risk of heart problems.     

Myocardial oxidative metabolic supply-demand relationships in patients with nonischemic dilated cardiomyopathy.

BACKGROUND: Nonischemic dilated cardiomyopathy (NIDCM) is associated with left ventricular remodeling, hypertrophy, and mitochondrial metabolic abnormalities in vitro. We evaluated the hypothesis that energy supply, as judged by the rate of myocardial oxidative metabolism, is inadequate to meet oxygen demand in patients with NIDCM compared with normal subjects. METHODS AND RESULTS: We used positron emission tomography to determine the myocardial carbon 11 acetate decay rate (kmono) as an index of energy supply, and we compared kmono with the rate-pressure product (RPP) as an index of metabolic demand in 7 patients with NIDCM and 7 normal subjects. The mean kmono value (SEM) was 0.060 +/- 0.006 min(-1) in NIDCM patients versus 0.054 +/- 0.002 in normal subjects (P = not significant). The RPP was 9949 +/- 931 beats/min.mm Hg in NIDCM patients and 6521 +/- 476 in normal subjects (P = .007). The relationship of kmono to this index of demand (kmono/RPP) was 6.2 x 10(-6) in NIDCM patients but was 8.5 x 10(-6) in normal subjects (P = .003). Thus RPP, as an index of myocardial oxygen demand, was poorly matched by the rate of oxidative metabolism in those patients with NIDCM. The kmono was closely related to RPP in normal subjects (r = 0.83, P = .02) but not in NIDCM patients. Furthermore, there was no significant relationship between kmono and wall stress as another index of oxygen demand. CONCLUSIONS: These results are consistent with a mitochondrial metabolic abnormality in heart failure. This metabolic mismatch detected by positron emission tomography may contribute to the pathophysiology of congestive heart failure and left ventricular remodeling.     

High rate of positive lymph nodes in T1a gallbladder cancer does not translate to decreased survival: a population-based,propensity score adjusted analysis

Background

Current consensus guidelines suggest that gallbladder cancer (GBC) patients with resected T1a disease can be observed while patients with T1b or greater lesions should undergo lymphadenectomy (LNE). The primary aim of this study was to critically explore the impact of LNE in early-stage GBC on overall survival (OS) on a population-based level.

Targeting Notch signaling in autoimmune and lymphoproliferative disease

Patients with autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosis (SLE) have T-cell dysregulation and produce abnormal, activated T lymphocytes and an atypical peripheral T-cell population, termed double negative T cells (DNTs). T-cell functions, including DNT transition in T-cell development and T-cell activation, are critically dependent on Notch signaling. We hypothesized that inhibiting Notch signaling would be effective in ALPS and SLE by reducing the production of abnormal DNTs and by blocking aberrant T-cell activation. We tested this hypothesis using murine models of ALPS and SLE. Mice were randomized to treatment with the notch pathway inhibitor (gamma-secretase inhibitor), N-S-phenyl-glycine-t-butyl ester (DAPT), or vehicle control. Response to treatment was assessed by measurement of DNTs in blood and lymphoid tissue, by monitoring lymph node and spleen size with ultrasound, by quantifying cytokines by bead-array, by ELISA for total IgG and anti-double-stranded DNA (dsDNA) specific antibodies, and by histopathologic assessment for nephritis. We found a profound and statistically significant decrease in all disease parameters, comparing DAPT-treated mice to controls. Using a novel dosing schema, we avoided the reported toxicities of gamma-secretase inhibitors. Inhibiting the Notch signaling pathway may thus present an effective, novel, and well-tolerated treatment for autoimmune and lymphoproliferative diseases.