Brain-reactive autoantibodies prevalent in human sera increase intraneuronal amyloid-β(1-42) deposition

Previous studies have reported immunoglobulin-positive neurons in Alzheimer's disease (AD) brains, an observation indicative of blood-brain barrier (BBB) breakdown. Recently, we demonstrated the nearly ubiquitous presence of brain-reactive autoantibodies in human sera. The significance of these observations to AD pathology is unknown. Here, we show that IgG-immunopositive neurons are abundant in brain regions exhibiting AD pathology, including intraneuronal amyloid-β(42) (Aβ(42)) and amyloid plaques, and confirm by western analysis that brain-reactive autoantibodies are nearly ubiquitous in human serum. To investigate a possible interrelationship between neuronal antibody binding and Aβ pathology, we tested the effects of human serum autoantibodies on the intraneuronal deposition of soluble Aβ(42) peptide in adult mouse neurons in vitro (organotypic brain slice cultures). Binding of human autoantibodies to mouse neurons dramatically increased the rate and extent of intraneuronal Aβ(42) accumulation in the mouse cerebral cortex and hippocampus. Additionally, individual sera exhibited variable potency related to their capacity to enhance intraneuronal Aβ(42) peptide accumulation and immunolabel neurons in AD brain sections. Replacement of human sera with antibodies targeting abundant neuronal surface proteins resulted in a comparable enhancement of Aβ(42) accumulation in mouse neurons. Overall, results suggest that brain-reactive autoantibodies are ubiquitous in the blood and that a defective BBB allows these antibodies to access the brain interstitium, bind to neuronal surfaces and enhance intraneuronal deposition of Aβ(42) in AD brains. Thus, in the context of BBB compromise, brain-reactive autoantibodies may be an important risk factor for the initiation and/or progression of AD as well as other neurodegenerative diseases.     

Program characteristics and organizational factors affecting the implementation of a school-based indicated prevention program

Reconnecting Youth (RY) is a school-based drug prevention program designed to address academic, substance use and mood management goals among youth at risk of dropping out of high school. This paper presents the organizational factors and RY program characteristics that either promoted or hindered the implementation of the program during a randomized controlled effectiveness trial in 10 schools in two school districts in the United States. Data were collected using surveys and interviews from teachers and school and district staff who participated in the implementation of the RY program in these schools. Results suggest that certain RY program characteristics made it difficult to implement. Small class size, resource-intensive procedures for student selection and recruitment and special training, qualities and skills needed to be an effective RY teacher meant that schools had to significantly change their usual practices to implement the program. Organizational barriers included a lack of financial resources and leadership support for program implementation, and low priority for non-academic courses for high-risk students. Transient student populations, staff turnover and district-wide scheduling and curriculum changes all resulted in high levels of organizational turbulence at most schools, further hindering program implementation.     

Spatial working memory as a cognitive endophenotype of schizophrenia: assessing risk for pathophysiological dysfunction

Research suggests that first-degree relatives and individuals with schizophrenia spectrum personality disorders (SSPD) may represent nonpenetrant carriers of the genetic diathesis for schizophrenia. This study examined visuospatial working memory (SWM) as a cognitive endophenotype of schizophrenia by expanding the concept of risk for pathophysiological dysfunction beyond overt psychosis. Risk was thus defined by familial status and the presence or absence of SSPD. SWM was assessed in the following groups, in order of decreasing likelihood of genetic vulnerability: 23 patients with schizophrenia, 17 SSPD relatives of patients with schizophrenia, 23 non-SSPD relatives of patients with schizophrenia, 14 SSPD community members with no family history of psychosis, and 36 non-SSPD community members. SWM performance during a computer task was quantified by A-Prime. Relative risk ratios for SWM deficits were compared among the groups. Compared with community non-SSPD volunteers, relative risk (RR) of SWM deficits was significantly elevated in patients with schizophrenia (RR = 3.76, p = .002) and SSPD family members (RR = 2.97, p = .027), but not in the family non-SSPD (RR = 1.88, p = .241) or community SSPD (RR = 1.03, p = .971) groups. The pattern of SWM performance deficits reflected the proposed model of latent genetic liability, upholding SWM as a viable cognitive endophenotype. The results underscore the importance of including both familial liability and the schizophrenia spectrum when considering risk for schizophrenia and schizophrenia-related traits. This is particularly relevant for research efforts to identify pathophysiological components of the disease.     

Echocardiographic assessment of coronary blood flow velocity during controlled hypotensive anesthesia with nitroglycerin

OBJECTIVE: To determine the effect of nitroglycerin on coronary blood flow velocity during controlled hypotensive anesthesia in humans. DESIGN: Internally controlled prospective study. SETTING: Single university hospital. PARTICIPANTS: Twenty American Society of Anesthesiologists class I and II patients undergoing general anesthesia for surgical resection of a malignancy. INTERVENTIONS: General anesthesia was induced with thiopental, fentanyl, and succinylcholine and maintained with isoflurane and vecuronium. Transesophageal echocardiography was used to evaluate left ventricular wall motion and blood flow velocity in the left anterior descending coronary artery. Intravenous nitroglycerin was used to reduce systolic arterial pressure to 60 to 70 mmHg. Intravenous albumin 5% was administered to maintain pulmonary capillary wedge pressure >5 mmHg. MEASUREMENTS AND MAIN RESULTS: The left anterior descending coronary artery was visualized clearly in 16 of 20 patients. At a mean nitroglycerin dose of 16+/-14 microg/kg/min, peak diastolic left anterior descending flow velocity increased significantly from 32.5+/-10.3 cm/sec to 44.7+/-14.6 cm/sec (p = 0.0103). None of the patients developed any ST-segment changes. CONCLUSIONS: During nitroglycerin-induced hypotensive anesthesia, coronary blood flow as assessed by peak diastolic left anterior descending flow velocity is preserved or increased in most patients. Increases in left anterior descending flow velocity are predictably achieved only at nitroglycerin doses >5 microg/kg/min. Intraoperative transesophageal echocardiography is useful in monitoring coronary flow velocity responses to controlled hypotensive anesthesia.     

Work related stress among gynecologic oncologists

Objective

Up to one third of oncologists experience burnout. The objective was to determine correlates of work related stress in gynecologic oncologists (GOs).

Methods

Using an online tool, we surveyed 273 members of the International Gynecologic Cancer (IGCS) Society (60% from North America) to examine demographic, psychological and spiritual correlates of work related stress (WRS) and burnout. Measures of death anxiety (DA) and locus of control (LOC) were also administered.

Results

WRS did not correlate with religion, religiosity, race, or gender, but did correlate with DA (r = 0.23, p = 0.0006). WRS was also associated with younger age (p = 0.01) and fewer years out of training (p = 0.0286), higher scores on LOC Chance (r = 0.18, p = 0.007), higher scores on Powerful Other (r = 0.30, p < 0.0001), and lower scores on LOC Internality (r = − 0.30, p < 0.0001).

Conclusion

Responses from younger and less experienced GOs, correlate with higher WRS scores especially if their LOC is weighted toward chance and powerful others. Responses of GO's with these two characteristics also correlate with higher DA scores and reports of difficulty talking about death.