Monoclonal Antibody Identification of Subpopulations of Cerebral Cortical Neurons Affected in Alzheimer disease

Neuronal degeneration is one of the hallmarks of Alzheimer disease (AD). Given the paucity of molecular markers available for the identification of neuronal subtypes, the specificity of neuronal loss within the cerebral cortex has been difficult to evaluate. With a panel of four monoclonal antibodies (mAbs) applied to central nervous system tissues from AD patients, we have immunocytochemically identified a population of vulnerable cortical neurons; a subpopulation of pyramidal neurons is recognized by mAbs 3F12 and 44.1 in the hippocampus and neocortex, and clusters of multipolar neurons in the entorhinal cortex reactive with mAb 44.1 show selective degeneration. Closely adjacent stellate-like neurons in these regions, identified by mAb 6A2, show striking preservation in AD. The neurons recognized by mAbs 3F12 and 44.1, to the best of our knowledge, do not comprise a single known neurotransmitter system. mAb 3A4 identifies a phosphorylated antigen that is undetectable in normal brain but accumulates early in the course of AD in somas of vulnerable neurons. Antigen 3A4 is distinct from material reactive with thioflavin S or antibody generated against paired helical filaments. Initially, antigen 3A4 is localized to neurons in the entorhinal cortex and subiculum, later in the association neocortex, and, ultimately in cases of long duration, in primary sensory cortical regions. mAb 3F12 recognizes multiple bands on immunoblots of homogenates of normal and Ad cortical tissues, whereas mAb 3A4 does not bind to immunoblots containing neurofilament proteins or brain homogenates from AD patients. Ultrastructurally, antigen 3A4 is localized to paired-helical filaments. Using these mAbs, further molecular characterization of the affected cortical neurons is now possible

Evaluation of extension of breast screening to women aged 65–70 in England using screening performance measures

The objective of this study was to investigate screening performance measures in the English screening units that began inviting women aged 65–70 between 1 April 2001 and 1 April 2004. We analysed results after each unit commenced inviting women aged 65–70. In addition, we analysed data from units that invited this age group for a second time between 1 April 2004 and 31 March 2007. Results for women aged 65–70 were compared to women aged 50–64 and 60–64. Average uptake was 72.8% for women aged 65–70 and 76.7% for women aged 50–64. For women screened within the last 5 years, uptake was 88.7% for older women and 89.1% for younger women. For women previously screened within 5 years the invasive cancer detection rate was 17% higher in the 65–70 age group than in the 60–64 age group. The rates of recall to assessment and PPV were 3.5 and 27.6% in women aged 65–70 and 3.4 and 24.6% in women aged 50–64 respectively. These results suggest that, as in the earlier demonstration studies, uptake rates remain high in older women, and many more older women attend following an invitation than had previously self-referred. The cancer detection rate is higher in this older age group, whereas rates of recall are generally similar to those in younger women; consequently the PPV is also higher in older women

Detection of Non-Symmetrical Damage in Smart Plate-Like Structures

A two-dimensional model for in-plane vibrations of a cantilever plate with a non-symmetrical damage is used in the context of defect identification in materials with piezoelectric ceramic patches bonded to their surface. These patches can act both as actuators and sensors in a self-analyzing fashion, which is a characteristic of smart materials. A Galerkin method is used to approximate the dynamic response of these structures. The natural frequency shifts due to the damage are estimated numerically and compared to experimental data obtained from tests on cantilever aluminum plate-like structures damaged at different locations with defects of different depths. The damage location and extent are determined by an enhanced least square identification method. Efficacy of the frequency shift based algorithms is demonstrated using experimental data

Association of a Communication Training Program With Use of Antipsychotics in Nursing Homes

Importance: Off-label antipsychotic prescribing in nursing homes (NHs) is common and is associated with increased risk of mortality in older adults. Prior large-scale, controlled trials in the NH setting failed to show meaningful reductions in antipsychotic use. Objective: To quantify the influence of a large-scale communication training program on NH antipsychotic use called OASIS. Design, Setting, and Participants: This investigation was a quasi-experimental longitudinal study of NHs in Massachusetts enrolled in the OASIS intervention. Participants were residents living in NHs between March 1, 2011, and August 31, 2013. The data were analyzed from December 2015, to March 2016, and from November through December 2016. Exposures: The OASIS educational program targets all NH staff (direct care and nondirect care) using a train-the-trainer model. The program goals were to reframe challenging behaviors of residents with cognitive impairment as the communication of unmet needs, to train staff to anticipate resident needs, and to integrate resident strengths into daily care plans. Main Outcomes and Measures: This study used an interrupted time series model of facility-level prevalence of antipsychotic medication use, other psychotropic medication use (antidepressants, anxiolytics, and hypnotics), and behavioral disturbances to evaluate the intervention\u27s effectiveness in participating facilities compared with control NHs in Massachusetts and New York. The 18-month preintervention (baseline) period was compared with a 3-month training period, a 6-month implementation period, and a 3-month maintenance period. Results: This study included 93 NHs enrolled in the OASIS intervention (27 of which had a high prevalence of antipsychotic use) compared with 831 nonintervention NHs. Among OASIS facilities, prevalences of atypical antipsychotic prescribing were 34.1% at baseline and 26.5% at the study end (absolute reduction of 7.6% and relative reduction of 22.3%) compared with a drop of 22.7% to 18.8% in the comparison facilities (absolute reduction of 3.9% and relative reduction of 17.2%). In the OASIS implementation phase, NHs experienced a reduction in antipsychotic use prevalence among OASIS facilities (-1.20%; 95% CI, -1.85% to -0.09% per quarter) greater than that among non-OASIS facilities (-0.23%; 95% CI, -0.47% to 0.01% per quarter), resulting in a net OASIS influence of -0.97% (95% CI, -1.85% to -0.09%; P = .03). A difference in trend was not sustained in the maintenance phase (difference of 0.93%; 95% CI, -0.66% to 2.54%; P = .48). No increases in other psychotropic medication use or behavioral disturbances were observed. Conclusions and Relevance: Antipsychotic use prevalence declined during OASIS implementation of the intervention, but the decreases did not continue in the maintenance phase. Other psychotropic medication use and behavioral disturbances did not increase. This study adds evidence for nonpharmacological programs to treat behavioral and psychological symptoms of dementia

The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via Gαi signalling

Oxytocin (OT) plays an important role in the onset of human labour by stimulating uterine contractions and promoting prostaglandin/inflammatory cytokine synthesis in amnion via oxytocin receptor (OTR) coupling. The OTR-antagonist, Atosiban, is widely used as a tocolytic for the management of acute preterm labour. We found that in primary human amniocytes, Atosiban (10 μM) signals via PTX-sensitive Gαi to activate transcription factor NF-κB p65, ERK1/2, and p38 which subsequently drives upregulation of the prostaglandin synthesis enzymes, COX-2 and phospho-cPLA2 and excretion of prostaglandins (PGE2) (n = 6; p < 0.05, ANOVA). Moreover, Atosiban treatment increased expression and excretion of the inflammatory cytokines, IL-6 and CCL5. We also showed that OT-simulated activation of NF-κB, ERK1/2, and p38 and subsequent prostaglandin and inflammatory cytokine synthesis is via Gαi−2 and Gαi−3 but not Gαq, and is not inhibited by Atosiban. Activation or exacerbation of inflammation is not a desirable effect of tocolytics. Therefore therapeutic modulation of the OT/OTR system for clinical management of term/preterm labour should consider the effects of differential G-protein coupling of the OTR and the role of OT or selective OTR agonists/antagonists in activating proinflammatory pathways

Myometrial transcriptional signatures of human parturition

The process of parturition involves the transformation of the quiescent myometrium (uterine smooth muscle) to the highly contractile laboring state. This is thought to be driven by changes in gene expression in myometrial cells. Despite the existence of multiple myometrial gene expression studies, the transcriptional programs that initiate labor are not known. Here, we integrated three transcriptome datasets, one novel (NCBI Gene Expression Ominibus: GSE80172) and two existing, to characterize the gene expression changes in myometrium associated with the onset of labor at term. Computational analyses including classification, singular value decomposition, pathway enrichment, and network inference were applied to individual and combined datasets. Outcomes across studies were integrated with multiple protein and pathway databases to build a myometrial parturition signaling network. A high-confidence (significant across all studies) set of 126 labor genes were identified and machine learning models exhibited high reproducibility between studies. Labor signatures included both known (interleukins, cytokines) and unknown (apoptosis, , cell proliferation/differentiation) pathways while cyclic AMP signaling and muscle relaxation were associated with non-labor. These signatures accurately classified and characterized the stages of labor. The data-derived parturition signaling networks provide new genes/signaling interactions to understand phenotype-specific processes and aid in future studies of parturition