Integrating primary care into a community mental health center.

Our initiation of a reverse-integration practice model revealed numerous advantages and rewards, as well as many challenges, for which we found solutions.

Disseminated Microinfarctions with Cerebral Microbleeds.

Disseminated microinfarctions are uncommonly encountered in clinical practice. Here we describe a patient with long-standing cerebral microbleeds who developed acute cognitive decline in the setting of acute hypotension. Magnetic resonance imaging showed acute disseminated microinfarctions, with no change in microbleeds. This case emphasizes the important relationship between ischemic and hemorrhagic microvascular disease of the brain, especially in the setting of acute blood pressure changes compounding preexisting microvascular injury.

Teleneurology for Veterans in a Major Metropolitan Area.

BACKGROUND: The recent growth in telehealth has been facilitated by the need to deliver healthcare to patients living in remote or rural areas. In contrast, the role of telehealth in more urban settings is less clear. A teleneurology program was established in 2011 at the Tibor Rubin VA Medical Center (TRVAMC) in Long Beach, California. A review of teleneurology encounters was conducted to assess the feasibility of applying this telehealth modality to patients with chronic neurological disorders living in an urban setting. METHODS: Teleneurology encounters were conducted by clinical video telehealth (CVT) between a provider at the TRVAMC and patients at local community-based outpatient clinics from November 2011 to December 2014. In a random sampling of veterans, they were asked to complete a patient satisfaction survey. RESULTS: A total of 745 teleneurology encounters were performed including 570 unique patients. Veterans with a broad range of neurological disorders were seen, including Parkinson's disease, headaches, epilepsy, dementia, cerebrovascular disease, peripheral nervous system disorders, multiple sclerosis, and other problems such as dizziness and paresthesia. Compared with patients in face-to-face clinics, patients in teleneurology clinics consistently kept their appointments. Technical problems were rare and easily resolved. The majority of patients were satisfied with the care they received through teleneurology, and preferred CVT rather than a face-to-face encounter. CONCLUSIONS: This report demonstrates the successful application of telehealth to evaluate and manage a diverse group of neurological disorders in an urban setting. Despite the relatively short distances involved, the majority of patients preferred telehealth over face-to-face encounters.

Nucleolar stress characterized by downregulation of nucleophosmin: a novel cause of neuronal degeneration.

Nucleophosmin (NPM) is a multifunctional nucleolar protein that has been linked with nucleolar stress. In non-neuronal cell lines, NPM may enhance or inhibit the activity of tumor suppressor p53, a major apoptotic protein. The relationship between NPM and p53 in the central nervous system (CNS) remains unknown. Here, we assessed the role of NPM in the CNS using a model of seizure-induced neurodegeneration. We show that NPM overexpression is neuroprotective against kainic acid-induced excitotoxicity, and that downregulation of NPM is pro-apoptotic in a p53-independent manner. These results suggest a key role for NPM in promoting neuronal survival and a novel mechanism of neuronal degeneration triggered by nucleolar stress.

Differential Expression of Redox Factor-1 Associated with Beta-Amyloid-Mediated Neurotoxicity.

Redox factor-1 (Ref-1), also known as HAP1, APE or APEX, is a multifunctional protein that regulates gene transcription as well as the response to oxidative stress. By interacting with transcription factors such as AP-1, NF-kappaB and p53, and directly participating in the cleavage of apurininic/apyrimidinic DNA lesions, Ref-1 plays crucial roles in both cell death signaling pathways and DNA repair, respectively. Oxidative stress induced by aggregated beta-amyloid (Abeta) peptide, altered DNA repair and transcriptional activation of cell death pathways have been implicated in the pathophysiology of Alzheimer's disease (AD). Here we show that varying concentrations of Abeta(1-42) differentially regulate Ref-1 expression, Ref-1 function and neuronal survival in vitro. Abeta (5.0 muM) caused a relatively rapid decrease in Ref-1 expression and activity associated with extensive DNA damage and neuronal degeneration. In contrast, Ref-1 induction occurred in cells exposed to Abeta (1.0 muM) without significant neuronal cell death. Abeta-induced attenuation of Ref-1 expression and endonuclease activity, and neuronal cell death were prevented by the anti-oxidant, catalase. Similar differential effects on Ref-1 expression and cell viability were observed in N2A neuroblastoma cells treated with either high or low dose hydrogen peroxide. These findings demonstrate the differential regulation of Ref-1 expression by varying degrees of oxidative stress. Parallels between the Ref-1 response to Abeta and H(2)O(2) suggest similarities between DNA repair pathways activated by different inducers of oxidative stress. In AD brain, colocalization of Ref-1 and Abeta the absence of significant DNA damage are consistent with the cell culture results and suggests that Ref-1 may play a more neuroprotective role under these conditions. Modulation of Ref-1 expression and activity by local variations in Abeta concentration may be an important determinant of neuronal vulnerability to oxidative stress in AD.

Amyloid-peptide vaccinations reduce {beta}-amyloid plaques but exacerbate vascular deposition and inflammation in the retina of Alzheimer's transgenic mice.

Alzheimer's disease (AD) is pathologically characterized by accumulation of beta-amyloid (Abeta) protein deposits and/or neurofibrillary tangles in association with progressive cognitive deficits. Although numerous studies have demonstrated a relationship between brain pathology and AD progression, the Alzheimer's pathological hallmarks have not been found in the AD retina. A recent report showed Abeta plaques in the retinas of APPswe/PS1DeltaE9 transgenic mice. We now report the detection of Abeta plaques with increased retinal microvascular deposition of Abeta and neuroinflammation in Tg2576 mouse retinas. The majority of Abeta-immunoreactive plaques were detected from the ganglion cell layer to the inner plexiform layer, and some plaques were observed in the outer nuclear layer, photoreceptor outer segment, and optic nerve. Hyperphosphorylated tau was labeled in the corresponding areas of the Abeta plaques in adjacent sections. Although Abeta vaccinations reduced retinal Abeta deposits, there was a marked increase in retinal microvascular Abeta deposition as well as local neuroinflammation manifested by microglial infiltration and astrogliosis linked with disruption of the retinal organization. These results provide evidence to support further investigation of the use of retinal imaging to diagnose AD and to monitor disease activity.

Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau.

Memory loss is the signature feature of Alzheimer's disease, and therapies that prevent or delay its onset are urgently needed. Effective preventive strategies likely offer the greatest and most widespread benefits. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance memory and synaptic plasticity. We evaluated the efficacy of nicotinamide, a competitive inhibitor of the sirtuins or class III NAD(+)-dependent HDACs in 3xTg-AD mice, and found that it restored cognitive deficits associated with pathology. Nicotinamide selectively reduces a specific phospho-species of tau (Thr231) that is associated with microtubule depolymerization, in a manner similar to inhibition of SirT1. Nicotinamide also dramatically increased acetylated alpha-tubulin, a primary substrate of SirT2, and MAP2c, both of which are linked to increased microtubule stability. Reduced phosphoThr231-tau was related to a reduction of monoubiquitin-conjugated tau, suggesting that this posttranslationally modified form of tau may be rapidly degraded. Overexpression of a Thr231-phospho-mimic tau in vitro increased clearance and decreased accumulation of tau compared with wild-type tau. These preclinical findings suggest that oral nicotinamide may represent a safe treatment for AD and other tauopathies, and that phosphorylation of tau at Thr231 may regulate tau stability.

Induction of DNA repair proteins, Ref-1 and XRCC1, in adult rat brain following kainic acid-induced seizures.

We evaluated the expression of DNA repair proteins, redox factor-1 (Ref-1) and X-ray repair cross-complementing protein 1 (XRCC1), relevant to neurodegeneration following kainic acid-induced seizures in rats. Neurons with oxidative DNA damage exhibited increased expression and colocalization of Ref-1 and XRCC1. Upregulation of DNA repair proteins was also associated with p53 induction and TUNEL. Coexpression of DNA repair proteins and cell death markers following seizures suggests that the DNA repair response may not be sufficient to prevent excitotoxin-induced neurodegeneration.

Immunohistochemical study of p53-associated proteins in rat brain following lithium-pilocarpine status epilepticus.

Activation of the p53-stress response pathway has been implicated in excitotoxic neuronal cell death. Recent studies have demonstrated an age-dependent induction of both p53 mRNA and protein in the rat brain following lithium-pilocarpine-mediated status epilepticus (LPSE). We investigated whether other proteins that have been shown to participate in the p53 cascade are induced by LPSE. We used immunohistochemistry to examine the expression of Mdm2, Bax, CD95/Fas/APO-1, ATM, Ref-1 and ubiquitin. A significant increase in nuclear Mdm2 immunoreactivity, which colocalized with p53, was observed in cells within hippocampal pyramidal cell layers, dentate gyrus, piriform cortex, amygdala and thalamus. Dual immunofluorescence microscopy revealed a reduction in free ubiquitin expression in cells with p53 and Mdm2 accumulation. Increased immunoreactivity for CD95/Fas/APO-1 and Bax was also detected in the same p53-positive cells. Moreover, expression of Ref-1 and ATM, which are involved in the response to oxidative stress-induced DNA damage and regulation of p53 function, were increased. Colocalization of Ref-1 and p53 suggests that Ref-1 might activate p53 function in LPSE-induced neurodegeneration. In contrast, ATM immunoreactivity was predominantly cytoplasmic suggesting that ATM may not directly modulate p53 activity in injured neurons. These results extend our previous observations with regard to activation and stabilization of p53 in injured central nervous system neurons. The data indicate that p53 induction following LPSE may activate downstream pro-apoptotic genes leading to neurodegeneration.

Differential induction of p53 in immature and adult rat brain following lithium-pilocarpine status epilepticus.

Activation of the tumor suppressor gene, p53, has been strongly implicated in selective neuronal cell death. This study investigated p53 expression in the immature and adult rat brain following status epilepticus induced by the administration of lithium-pilocarpine (LPSE). Both p53 mRNA and protein were examined in relation to neuronal degeneration using in situ hybridization and immunohistochemistry, respectively. Injured cells with eosinophilic cytoplasm with increased p53 mRNA were observed in hippocampal subfields, piriform cortex, amygdala and thalamus. p53 mRNA levels reached a peak by 8 h and returned to baseline by 24 h after the onset of LPSE. The magnitude of p53 mRNA induction was greatest in 21-day-old rats. In contrast to the cellular expression pattern of p53 mRNA, immunohistochemistry demonstrated that p53 protein was increased in all of the eosinophilic cells. Further, double-labeling studies revealed that p53 protein was elevated in neurons that were degenerating. This was supported by colocalization of activated caspase 3 in some cells with damaged DNA. These results provide additional evidence for a critical role for the p53 pathway in excitotoxic neuronal cell death due to status epilepticus.