"What do you think about nephrology?" A national survey of internal medicine residents.

BACKGROUND: Interest in nephrology has been declining among internal medicine residents but the reasons behind this observation are not well characterized. Our objective was to evaluate factors influencing residents' choice of subspecialty. METHODS: This is a mixed-method QUAL-QUAN design study that used the results of our previously published qualitative analysis on residents' perception of nephrology to create and pilot a questionnaire of 60 questions. The final questionnaire was distributed to 26 programs across the United States and a total of 1992 residents. We calculated response rates and tabulated participant characteristics and percentage of participant responses. We categorized choice of fellowship into 2 medical categories (Highly Sought After vs. Less Sought After) and fitted a logistic regression model of choosing a highly vs. less sought after fellowship. RESULTS: Four hundred fifteen out of 1992 (21%) US residents responded to the survey. Of the 268 residents planning to pursue fellowship training, 67 (25%) selected a less sought after fellowship. Female sex was associated with significantly higher odds of selecting a less sought after fellowship (OR = 2.64, 95% CI: 1.47, 4.74). Major factors deterring residents from pursuing nephrology were perception of inadequate financial compensation, broad scope of clinical practice and complexity of patient population. We observed a decline in exposure to nephrology during the clinical years of medical school with only 35.4% of respondents rotating in nephrology versus 76.8% in residency. The quality of nephrology education was rated less positively during clinical medical school years (median of 50 on a 0-100 point scale) compared to the pre-clinical years (median 60) and residency (median 75). CONCLUSION: Our study attempts to explain the declining interest in nephrology. Results suggest potential targets for improvement: diversified trainee exposure, sub-specialization of nephrology, and increased involvement of nephrologists in the education of trainees.

An epigenetic blockade of cognitive functions in the neurodegenerating brain.

Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer's disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer's-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer's disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.

miR-149 and miR-29c as candidates for bipolar disorder biomarkers.

Bipolar disorder (BD) is a common, recurring psychiatric illness with unknown pathogenesis. Recent studies suggest that microRNA (miRNA) levels in brains of BD patients are significantly altered, and these changes may offer insight into BD pathology or etiology. Previously, we observed significant alterations of miR-29c levels in extracellular vesicles (EVs) extracted from prefrontal cortex (Brodmann area 9, BA9) of BD patients. In this study, we show that EVs extracted from the anterior cingulate cortex (BA24), a crucial area for modulating emotional expression and affect, have increased levels of miR-149 in BD patients compared to controls. Because miR-149 has been shown to inhibit glial proliferation, increased miR-149 expression in BA24-derived EVs is consistent with the previously reported reduced glial cell numbers in BA24 of patients diagnosed with either familial BD or familial major depressive disorder. qPCR analysis of laser-microdissected neuronal and glial cells from BA24 cortical samples of BD patients verified that the glial, but not neuronal, population exhibits significantly increased miR-149 expression. Finally, we report altered expression of both miR-149 and miR-29c in EVs extracted from brains of Flinders Sensitive Line rats, a well-validated animal model exhibiting depressive-like behaviors and glial (astrocytic) dysfunction. These findings warrant future investigations into the potential of using EV miRNA signatures as biomarkers to further enhance the biological definition of BD. © 2017 Wiley Periodicals, Inc.

Detection of TDP-43 oligomers in frontotemporal lobar degeneration-TDP.

OBJECTIVE: The proteinaceous inclusions in TDP-43 proteinopathies such as frontotemporal lobar degeneration (FTLD)-TDP are made of high-molecular-weight aggregates of TDP-43. These aggregates have not been classified as amyloids, as prior amyloid staining results were not conclusive. Here we used a specific TDP-43 amyloid oligomer antibody called TDP-O to determine the presence and abundance of TDP-43 oligomers among different subtypes of FTLD-TDP as well as in hippocampal sclerosis (HS), which represents a non-FTLD pathology with TDP-43 inclusions. METHODS: Postmortem tissue from the hippocampus and anterior orbital gyrus from 54 prospectively assessed and diagnosed subjects was used for immunostaining with TDP-O. Electron microscopy was used to assess the subcellular locations of TDP-O-decorated structures. RESULTS: TDP-43 inclusions staining with TDP-O were present in FTLD-TDP and were most conspicuous for FTLD-TDP type C, the subtype seen in most patients with semantic variant primary progressive aphasia. TDP-O immunoreactivity was absent in the hippocampus of HS patients despite abundant TDP-43 inclusions. Ultrastructurally, TDP-43 oligomers resided in granular or tubular structures, frequently in close proximity to, but not within, neuronal lysosomes. INTERPRETATION: TDP-43 forms amyloid oligomers in the human brain, which may cause neurotoxicity in a manner similar to other amyloid oligomers. Oligomer formation may contribute to the conformational heterogeneity of TDP-43 aggregates and mark the different properties of TDP-43 inclusions between FTLD-TDP and HS.

Myelin basic protein associates with AßPP, Aß1-42, and amyloid plaques in cortex of Alzheimer's disease brain.

The goal of this study was to show that myelin and axons in cortical gray matter are damaged in Alzheimer's disease (AD) brain. Superior temporal gyrus gray matter of AD patients (9 male, 14 female) was compared to cognitively normal controls (8 male, 7 female). Myelin basic protein (MBP) and a degraded myelin basic protein complex (dMBP) were quantified by Western blot. Brain sections were immunostained for MBP, dMBP, axonal neurofilament protein (NF), autophagy marker microtubule-associated proteins 1A/B light chain 3B precursor (LC3B), amyloid-ß protein precursor (AßPP), and amyloid markers amyloid ß1-42 (Aß1-42) and FSB. Co-immunoprecipitation and mass spectroscopy evaluated interaction of AßPP/Aß1-42 with MBP/dMBP. Evidence of axonal injury in AD cortex included appearance of AßPP in NF stained axons, and NF at margins of amyloid plaques. Evidence of myelin injury in AD cortex included (1) increased dMBP in AD gray matter compared to control (p < 0.001); (2) dMBP in AD neurons; and (3) increased LC3B that co-localized with MBP. Evidence of interaction of AßPP/Aß1-42 with myelin or axonal components included (1) greater binding of dMBP with AßPP in AD brain; (2) MBP at the margins of amyloid plaques; (3) dMBP co-localized with Aß1-42 in the core of amyloid plaques in AD brains; and (4) interactions between Aß1-42 and MBP/dMBP by co-immunoprecipitation and mass spectrometry. We conclude that damaged axons may be a source of AßPP. dMBP, MBP, and NF associate with amyloid plaques and dMBP associates with AßPP and Aß1-42. These molecules could be involved in formation of amyloid plaques.

Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients.

Exosomes are cellular secretory vesicles containing microRNAs (miRNAs). Once secreted, exosomes are able to attach to recipient cells and release miRNAs potentially modulating the function of the recipient cell. We hypothesized that exosomal miRNA expression in brains of patients diagnosed with schizophrenia (SZ) and bipolar disorder (BD) might differ from controls, reflecting either disease-specific or common aberrations in SZ and BD patients. The sources of the analyzed samples included McLean 66 Cohort Collection (Harvard Brain Tissue Resource Center), BrainNet Europe II (BNE, a consortium of 18 brain banks across Europe) and Boston Medical Center (BMC). Exosomal miRNAs from frozen postmortem prefrontal cortices with well-preserved RNA were isolated and submitted to profiling by Luminex FLEXMAP 3D microfluidic device. Multiple statistical analyses of microarray data suggested that certain exosomal miRNAs were differentially expressed in SZ and BD subjects in comparison to controls. RT-PCR validation confirmed that two miRNAs, miR-497 in SZ samples and miR-29c in BD samples, have significantly increased expression when compared to control samples. These results warrant future studies to evaluate the potential of exosome-derived miRNAs to serve as biomarkers of SZ and BD.

Increased expression of TrkB and Capzb2 accompanies preserved cognitive status in early Alzheimer disease pathology.

Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) may influence brain reserve, the ability of the brain to tolerate pathological changes without significant decline in function. Here, we explore whether a specifically vulnerable population of human neurons shows a compensatory response to the neuropathological changes of Alzheimer disease (AD) and whether that response depends on an upregulation of the BDNF pathway. We observed increased neuronal TrkB expression associated with early-stage AD pathology (Braak and Braak stages I-II) in hippocampal CA1 region samples from cognitively intact Framingham Heart Study subjects (n = 5) when compared with cognitively intact individuals with no neurofibrillary tangles (n = 4). Because BDNF/TrkB signaling affects memory formation and retention through modification of the actin cytoskeleton, we examined the expression of actin capping protein ß2 (Capzb2), a marker of actin cytoskeleton reorganization. Capzb2 expression was also significantly increased in CA1 hippocampal neurons of cognitively intact subjects with early-stage AD pathology. Our data suggest that increased expression of TrkB and Capzb2 accompanies adequate brain reserve in the initial stages of AD pathology. In subsequent stages of AD, the higher levels of TrkB and Capzb2 expression achieved may not be sufficient to prevent cognitive decline.

Capzb2 PROTEIN EXPRESSION IN THE BRAINS OF PATIENTS DIAGNOSED WITH ALZHEIMER'S DISEASE AND HUNTINGTON'S DISEASE.

The silencing of actin capping protein ß2, Capzb2, by RNAi in developing cultured neurons results in short, dystrophic neurites reminiscent of cytoskeletal changes seen in diverse neurodegenerative diseases, including Alzheimer's disease (AD) and Huntington's disease (HD). Actin and tubulin are two major cytoskeletal proteins indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli. We have previously shown that Capzb2 binds tubulin and, in the presence of microtubule- associated protein tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons results in short neurites with abnormal growth cones. Decreased neurite length is found in both AD and HD. In the first step towards uncovering the possible role of Capzb2 in these diseases, we studied Capzb2 protein expression in the postmortem brains of AD and HD patients. To determine whether disease-specific changes in Capzb2 protein accompany the progression of neurodegeneration, we performed Western Blot analysis of prefrontal cortices (PFC) and hippocampi (HPC) in AD patients and of PFC and heads of caudate nuclei (HCN) in HD patients. Our results show disease- and area-specific dynamics in the levels of Capzb2 protein expression in the progressive stages of AD and HD.

Modulators of cytoskeletal reorganization in CA1 hippocampal neurons show increased expression in patients at mid-stage Alzheimer's disease.

During the progression of Alzheimer's disease (AD), hippocampal neurons undergo cytoskeletal reorganization, resulting in degenerative as well as regenerative changes. As neurofibrillary tangles form and dystrophic neurites appear, sprouting neuronal processes with growth cones emerge. Actin and tubulin are indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli. We have previously shown that actin capping protein beta2 subunit, Capzb2, binds tubulin and, in the presence of tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons resulted in short, dystrophic neurites, seen in neurodegenerative diseases including AD. Here we demonstrate the statistically significant increase in the Capzb2 expression in the postmortem hippocampi in persons at mid-stage, Braak and Braak stage (BB) III-IV, non-familial AD in comparison to controls. The dynamics of Capzb2 expression in progressive AD stages cannot be attributed to reactive astrocytosis. Moreover, the increased expression of Capzb2 mRNA in CA1 pyramidal neurons in AD BB III-IV is accompanied by an increased mRNA expression of brain derived neurotrophic factor (BDNF) receptor tyrosine kinase B (TrkB), mediator of synaptic plasticity in hippocampal neurons. Thus, the up-regulation of Capzb2 and TrkB may reflect cytoskeletal reorganization and/or regenerative response occurring in hippocampal CA1 neurons at a specific stage of AD progression.