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Background: Impairments in certain cognitive processes (e.g., working memory) are typically most pronounced in schizophrenia (SZ), intermediate in bipolar disorder, and least in major depressive disorder. Given that working memory depends, in part, on neural circuitry that includes pyramidal cells in layer 3 (L3) and layer 5 (L5) of the dorsolateral prefrontal cortex (DLPFC), we sought to determine if transcriptome alterations in these neurons were shared or distinctive for each diagnosis., Methods: Pools of L3 and L5 pyramidal cells in the DLPFC were individually captured by laser microdissection from 19 matched tetrads of unaffected comparison subjects and subjects with SZ, bipolar disorder, and major depressive disorder, and the messenger RNA was subjected to transcriptome profiling by microarray., Results: In DLPFC L3 and L5 pyramidal cells, transcriptome alterations were numerous in subjects with SZ, but rare in subjects with bipolar disorder and major depressive disorder. The leading molecular pathways altered in subjects with SZ involved mitochondrial energy production and the regulation of protein translation. In addition, we did not find any significant transcriptome signatures related to psychosis or suicide., Conclusions: In concert, these findings suggest that molecular alterations in DLPFC L3 and L5 pyramidal cells might be characteristic of the disease processes operative in individuals diagnosed with SZ and thus might contribute to the circuitry alterations underlying cognitive dysfunction in individuals with SZ., (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Delirium is a potentially lethal condition of altered mental status, attention, and level of consciousness with an acute onset and fluctuating course. Its causes are multi-factorial, and its pathophysiology is not well understood; therefore clinical focus has been on prevention strategies and early detection. One patient evaluation technique in routine use is the Confusion Assessment Method (CAM): a relatively simple test resulting in 'positive', 'negative' or 'unable-to-assess' (UTA) ratings. Hartford Hospital nursing staff use the CAM regularly on all non-critical care units, and a high frequency of UTA was observed after reviewing several years of records. In addition, patients with UTA ratings displayed poor outcomes such as in-hospital mortality, longer lengths of stay, and discharge to acute and long term care facilities. We sought to better understand the use of UTA, especially outside of critical care environments, in order to improve delirium detection throughout the hospital. An unsupervised clustering approach was used with additional, concurrent assessment data available in the EHR to categorize patient visits with UTA CAMs. The results yielded insights into the most common situations in which the UTA rating was used (e.g. impaired verbal communication, dementia), suggesting potentially inappropriate ratings that could be refined with further evaluation and remedied with updated clinical training. Analysis of the patient clusters also suggested that unrecognized delirium may contribute to the poor outcomes associated with the use of UTA. This method of using temporally related high dimensional EHR data to illuminate a dynamic medical condition could have wider applicability., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Cognitive dysfunction in schizophrenia is associated with a lower density of dendritic spines on deep layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC). These alterations appear to reflect dysregulation of the actin cytoskeleton required for spine formation and maintenance. Consistent with this idea, altered expression of genes in the cell division cycle 42 (CDC42)-CDC42 effector protein (CDC42EP) signaling pathway, a key organizer of the actin cytoskeleton, was previously reported in DLPFC gray matter from subjects with schizophrenia. We examined the integrity of the CDC42-p21-activated serine/threonine protein kinases (PAK)-LIM domain-containing serine/threonine protein kinases (LIMK) signaling pathway in schizophrenia in a layer-specific and cell type-specific fashion in DLPFC deep layer 3., Methods: Using laser microdissection, samples of DLPFC deep layer 3 were collected from 56 matched pairs of subjects with schizophrenia and comparison subjects, and levels of CDC42-PAK-LIMK pathway messenger RNAs were measured by quantitative polymerase chain reaction. These same transcripts also were quantified by microarray in samples of individually microdissected deep layer 3 pyramidal cells from a subset of the same subjects and from monkeys exposed to antipsychotics., Results: Relative to comparison subjects, CDC42EP4, LIMK1, LIMK2, ARHGDIA, and PAK3 messenger RNA levels were significantly upregulated in subjects with schizophrenia in laminar and cellular samples. In contrast, CDC42 and PAK1 messenger RNA levels were significantly downregulated specifically in deep layer 3 pyramidal cells. These differences were not attributable to psychotropic medications or other comorbid factors., Conclusions: Findings from the present and prior studies converge on synergistic alterations in CDC42 signaling pathway that could destabilize actin dynamics and produce spine deficits preferentially in deep layer 3 pyramidal cells in schizophrenia., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)