Osteopontin/secreted phosphoprotein-1 harnesses glial-, immune-, and neuronal cell ligand-receptor interactions to sense and regulate acute and chronic neuroinflammation.

Osteopontin (OPN) also known by its official gene designation secreted phosphoprotein-1 (SPP1) is a fascinating, multifunctional protein expressed in a number of cell types that functions not only in intercellular communication, but also in the extracellular matrix (ECM). OPN/SPP1 possesses cytokine, chemokine, and signal transduction functions by virtue of modular structural motifs that provide interaction surfaces for integrins and CD44-variant receptors. In humans, there are three experimentally verified splice variants of OPN/SPP1 and CD44's ten exons are also alternatively spiced in a cell/tissue-specific manner, although very little is known about how this is regulated in the central nervous system (CNS). Post-translational modifications of phosphorylation, glycosylation, and localized cleavage by specific proteases in the cells and tissues where OPN/SPP1 functions, provides additional layers of specificity. However, the former make elucidating the exact molecular mechanisms of OPN/SPP1 function more complex. Flexibility in OPN/SPP1 structure and its engagement with integrins having the ability to transmit signals in inside-out and outside-in direction, is likely why OPN/SPP1 can serve as an early detector of inflammation and ongoing tissue damage in response to cancer, stroke, traumatic brain injury, pathogenic infection, and neurodegeneration, processes that impair tissue homeostasis. This review will focus on what is currently known about OPN/SPP1 function in the brain.

Kupyaphores are zinc homeostatic metallophores required for colonization of Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) endures a combination of metal scarcity and toxicity throughout the human infection cycle, contributing to complex clinical manifestations. Pathogens counteract this paradoxical dysmetallostasis by producing specialized metal trafficking systems. Capture of extracellular metal by siderophores is a widely accepted mode of iron acquisition, and Mtb iron-chelating siderophores, mycobactin, have been known since 1965. Currently, it is not known whether Mtb produces zinc scavenging molecules. Here, we characterize low-molecular-weight zinc-binding compounds secreted and imported by Mtb for zinc acquisition. These molecules, termed kupyaphores, are produced by a 10.8 kbp biosynthetic cluster and consists of a dipeptide core of ornithine and phenylalaninol, where amino groups are acylated with isonitrile-containing fatty acyl chains. Kupyaphores are stringently regulated and support Mtb survival under both nutritional deprivation and intoxication conditions. A kupyaphore-deficient Mtb strain is unable to mobilize sufficient zinc and shows reduced fitness upon infection. We observed early induction of kupyaphores in Mtb-infected mice lungs after infection, and these metabolites disappeared after 2 wk. Furthermore, we identify an Mtb-encoded isonitrile hydratase, which can possibly mediate intracellular zinc release through covalent modification of the isonitrile group of kupyaphores. Mtb clinical strains also produce kupyaphores during early passages. Our study thus uncovers a previously unknown zinc acquisition strategy of Mtb that could modulate host-pathogen interactions and disease outcome.

Metaorganismal choline metabolism shapes olfactory perception.

Microbes living in the intestine can regulate key signaling processes in the central nervous system that directly impact brain health. This gut-brain signaling axis is partially mediated by microbe-host-dependent immune regulation, gut-innervating neuronal communication, and endocrine-like small molecule metabolites that originate from bacteria to ultimately cross the blood-brain barrier. Given the mounting evidence of gut-brain crosstalk, a new therapeutic approach of "psychobiotics" has emerged, whereby strategies designed to primarily modify the gut microbiome have been shown to improve mental health or slow neurodegenerative diseases. Diet is one of the most powerful determinants of gut microbiome community structure, and dietary habits are associated with brain health and disease. Recently, the metaorganismal (i.e., diet-microbe-host) trimethylamine N-oxide (TMAO) pathway has been linked to the development of several brain diseases including Alzheimer's, Parkinson's, and ischemic stroke. However, it is poorly understood how metaorganismal TMAO production influences brain function under normal physiological conditions. To address this, here we have reduced TMAO levels by inhibiting gut microbe-driven choline conversion to trimethylamine (TMA), and then performed comprehensive behavioral phenotyping in mice. Unexpectedly, we find that TMAO is particularly enriched in the murine olfactory bulb, and when TMAO production is blunted at the level of bacterial choline TMA lyase (CutC/D), olfactory perception is altered. Taken together, our studies demonstrate a previously underappreciated role for the TMAO pathway in olfactory-related behaviors.

Azithromycin resistance in Escherichia coli and Salmonella from food-producing animals and meat in Europe.

OBJECTIVES: To characterize the genetic basis of azithromycin resistance in Escherichia coli and Salmonella collected within the EU harmonized antimicrobial resistance (AMR) surveillance programme in 2014-18 and the Danish AMR surveillance programme in 2016-19. METHODS: WGS data of 1007 E. coli [165 azithromycin resistant (MIC > 16 mg/L)] and 269 Salmonella [29 azithromycin resistant (MIC > 16 mg/L)] were screened for acquired macrolide resistance genes and mutations in rplDV, 23S rRNA and acrB genes using ResFinder v4.0, AMRFinder Plus and custom scripts. Genotype-phenotype concordance was determined for all isolates. Transferability of mef(C)-mph(G)-carrying plasmids was assessed by conjugation experiments. RESULTS: mph(A), mph(B), mef(B), erm(B) and mef(C)-mph(G) were detected in E. coli and Salmonella, whereas erm(C), erm(42), ere(A) and mph(E)-msr(E) were detected in E. coli only. The presence of macrolide resistance genes, alone or in combination, was concordant with the azithromycin-resistant phenotype in 69% of isolates. Distinct mph(A) operon structures were observed in azithromycin-susceptible (n = 50) and -resistant (n = 136) isolates. mef(C)-mph(G) were detected in porcine and bovine E. coli and in porcine Salmonella enterica serovar Derby and Salmonella enterica 1,4, [5],12:i:-, flanked downstream by ISCR2 or TnAs1 and associated with IncIγ and IncFII plasmids. CONCLUSIONS: Diverse azithromycin resistance genes were detected in E. coli and Salmonella from food-producing animals and meat in Europe. Azithromycin resistance genes mef(C)-mph(G) and erm(42) appear to be emerging primarily in porcine E. coli isolates. The identification of distinct mph(A) operon structures in susceptible and resistant isolates increases the predictive power of WGS-based methods for in silico detection of azithromycin resistance in Enterobacterales.

Clinical case report of intractable paroxysmal sympathetic hyperactivity in TANGO2 deficiency disorder.

TANGO2 deficiency disorder (TDD) is a neurodegenerative disease characterized by a broad and variable spectrum of clinical manifestations, even among individuals sharing the same pathogenic variants. Here, we report a severely affected individual with TDD presenting with intractable paroxysmal sympathetic hyperactivity (PSH). While progressive brain atrophy has been observed in TDD, PSH has not been reported. Despite comprehensive workup for an acute trigger, no definite cause was identified, and pharmacological interventions were ineffective to treat PSH. Ultimately care was redirected to comfort measures. This article expands the clinical phenotype of patients with TDD, highlights the possibility of PSH in these patients, and the need for continued research for better treatments of TDD.

Delivering Serious News in Pediatric Cardiology-A Pilot Program.

Pediatric cardiology fellows receive limited training on delivering serious news. This is a teachable skill through simulation-based communication. While studies have shown the use of communication courses in pediatrics, there have been none in pediatric cardiology. Pediatric cardiologists recognize the importance of good communication and desire further development of these skills. Based on an internal needs assessment, three cases were developed; fetal hypoplastic left heart syndrome, teenager with new hypertrophic cardiomyopathy, and young-adult with Fontan failure. A 4-h simulation course using evidence-based methods to teach delivering serious news was designed, consisting of a didactic session, case demonstration and small group case-based encounters with simulated patients. Trainees completed standardized pre/post-course surveys to assess perception of skill and preparedness. Paired survey responses were compared. Six pediatric cardiology fellows participated. Only 33% had received formal training in delivering serious news and 17% in techniques of responding to patient's emotions. The proportion of participants who felt good about their ability to deliver serious news and deal with a family's emotions increased from 0 to 83%. The proportion of participants who felt prepared to provide serious news about a patient's illness increased from 17 to 67%. Given the small number of participants, results were not statistically significant. All participants felt that the course was valuable in improving communication skills. A formal communication course increased perception of skill and preparedness among trainees. We provide an evidence-based framework and clinical cases for delivering serious news in pediatric cardiology, which is generalizable to other training programs.

Osteopontin Is an Integral Mediator of Cardiac Interstitial Fibrosis in Models of Human Immunodeficiency Virus Infection.

BACKGROUND: People with human immunodeficiency virus (HIV) have heightened incidence/risk of diastolic dysfunction and heart failure. Women with HIV have elevated cardiac fibrosis, and plasma osteopontin (Opn) is correlated to cardiac pathology. Therefore, this study provides mechanistic insight into the relationship between osteopontin and cardiac fibrosis during HIV infection. METHODS: Mouse embryonic fibroblasts (MEFs) modeled cardiac fibroblasts in vitro. Simian immunodeficiency virus (SIV)-infected macaques with or without antiretroviral therapy and HIV-infected humanized mice modeled HIV-associated cardiac fibrosis. RESULTS: Lipopolysaccharide-stimulated MEFs were myofibroblast-like, secreted cytokines, and produced Opn transcripts. SIV-infected animals had elevated plasma Opn at necropsy, full-length Opn in the ventricle, and ventricular interstitial fibrosis. Regression modeling identified growth differentiation factor 15, CD14+CD16+ monocytes, and CD163 expression on CD14+CD16+ monocytes as independent predictors of plasma Opn during SIV infection. HIV-infected humanized mice showed increased interstitial fibrosis compared to uninfected/untreated animals, and systemic inhibition of osteopontin by RNA aptamer reduced left ventricle fibrosis in HIV-infected humanized mice. CONCLUSIONS: Since Opn is elevated in the plasma and left ventricle during SIV infection and systemic inhibition of Opn reduced cardiac fibrosis in HIV-infected mice, Opn may be a potential target for adjunctive therapies to reduce cardiac fibrosis in people with HIV.

MBOAT7-driven lysophosphatidylinositol acylation in adipocytes contributes to systemic glucose homeostasis.

We previously demonstrated that antisense oligonucleotide-mediated knockdown of Mboat7, the gene encoding membrane bound O-acyltransferase 7, in the liver and adipose tissue of mice promoted high fat diet-induced hepatic steatosis, hyperinsulinemia, and systemic insulin resistance. Thereafter, other groups showed that hepatocyte-specific genetic deletion of Mboat7 promoted striking fatty liver and NAFLD progression in mice but does not alter insulin sensitivity, suggesting the potential for cell autonomous roles. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. We generated Mboat7 floxed mice and created hepatocyte- and adipocyte-specific Mboat7 knockout mice using Cre-recombinase mice under the control of the albumin and adiponectin promoter, respectively. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. The expression of Mboat7 in white adipose tissue closely correlates with diet-induced obesity across a panel of ∼100 inbred strains of mice fed a high fat/high sucrose diet. Moreover, we found that adipocyte-specific genetic deletion of Mboat7 is sufficient to promote hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, where Mboat7 plays a relatively minor role in maintaining arachidonic acid-containing PI pools, Mboat7 is the major source of arachidonic acid-containing PI pools in adipose tissue. Our data demonstrate that MBOAT7 is a critical regulator of adipose tissue PI homeostasis, and adipocyte MBOAT7-driven PI biosynthesis is closely linked to hyperinsulinemia and insulin resistance in mice.

Cerebellar Dysfunction as a Source of Dystonic Phenotypes in Mice.

There is now a substantial amount of compelling evidence demonstrating that the cerebellum may be a central locus in dystonia pathogenesis. Studies using spontaneous genetic mutations in rats and mice, engineered genetic alleles in mice, shRNA knockdown in mice, and conditional genetic silencing of fast neurotransmission in mice have all uncovered a common set of behavioral and electrophysiological defects that point to cerebellar cortical and cerebellar nuclei dysfunction as a source of dystonic phenotypes. Here, we revisit the Ptf1aCre/+;Vglut2flox/flox mutant mouse to define fundamental phenotypes and measures that are valuable for testing the cellular, circuit, and behavioral mechanisms that drive dystonia. In this model, excitatory neurotransmission from climbing fibers is genetically eliminated and, as a consequence, Purkinje cell and cerebellar nuclei firing are altered in vivo, with a prominent and lasting irregular burst pattern of spike activity in cerebellar nuclei neurons. The resulting impact on behavior is that the mice have developmental abnormalities, including twisting of the limbs and torso. These behaviors continue into adulthood along with a tremor, which can be measured with a tremor monitor or EMG. Importantly, expression of dystonic behavior is reduced upon cerebellar-targeted deep brain stimulation. The presence of specific combinations of disease-like features and therapeutic responses could reveal the causative mechanisms of different types of dystonia and related conditions. Ultimately, an emerging theme places cerebellar dysfunction at the center of a broader dystonia brain network.

A review of risks, adverse effects and mitigation strategies when delivering mental health services using telehealth.

BACKGROUND: This paper presents a scoping review of the peer-reviewed literature regarding reported risks, adverse effects and mitigation factors related to providing mental health services using telehealth. AIMS: The paper aims to describe risks and risk management strategies. METHODS: Publications were included if they reported upon risks, adverse events or mitigation factors experienced, hypothesised or discussed for: any population (any country, any age), service (any mental health services), intervention (telehealth), English language, 2010 to 10 July 2021, any publication type (commentary, research, policy), excluding protocol papers, and self-help tools. The following databases were searched: PsycINFO (from 2010 to 10 July 2021), MEDLINE (2010 to 10 July 2021) and the Cochrane Database from 2010 to 10 July 2021. RESULTS: The search strategy resulted in 1,497 papers and after exclusions a final 55 articles were selected. Results of this scoping review are presented in terms of types of risk, risk by client population, risk by modality (eg group therapy using telehealth) and risk management. CONCLUSIONS: Recommendations for future research include gathering and publishing more detailed information regarding near-miss and actual adverse events when delivering mental health assessment and care using telehealth. In clinical practice, training is required for potential adverse events, and to prevent them and reporting mechanisms in place to collate and learn from these.

Single midline incision approach for decompression of greater, lesser and third occipital nerves in migraine surgery.

BACKGROUND: The traditional approach for occipital migraine surgery encompasses three separate surgical incisions in the posterior neck to decompress the greater occipital nerves (GON), lesser occipital nerves (LON), and third occipital nerves (TON). Other incisions have been investigated, including singular transverse incisions. We sought to evaluate a single, vertical midline incision approach for decompression of all six occipital nerves. METHODS: Using 10 cadaveric hemi-sides (5 fresh cadaver head and necks). Anatomic landmarks and the location of the bilateral GON, LON, and TON were marked according to previous anatomic studies. A single, midline 9-cm incision was made, and lateral skin flaps were raised to decompress or avulse all six nerves. RESULTS: Through the midline incision, the GON and TON were identified at 3.5 and 6.2 cm, respectively, inferior to a line bisecting the external auditory canal (EAC) and 1.5 cm lateral to the midline. The LON was identified as 6-cm inferior and 6.5-cm medial to a line bisecting the EAC in the plane just above the investing layer of the deep cervical fascia until the posterior border of the sternocleidomastoid was encountered. The LON had the greatest amount of variation but was identified lateral to the posterior border of the SCM. CONCLUSIONS: A single midline incision approach allows for successful identification and decompression of all six occipital nerves in migraine surgery.

Effects of Manual Therapies and Resistance Exercise on Postexercise Hypotension in Women With Normal Blood Pressure.

ABSTRACT: Monteiro, ER, Pescatello, LS, Winchester, JB, Corrêa Neto, VG, Brown, AF, Budde, H, Marchetti, PH, Silva, JG, Vianna, JM, and Novaes, JdS. Effects of manual therapies and resistance exercise on postexercise hypotension in women with normal blood pressure. J Strength Cond Res 36(4): 948-954, 2022-The purpose of this investigation was to examine the acute effects of resistance exercise (RE) and different manual therapies (static stretching and manual massage [MM]) performed separately or combined on blood pressure (BP) responses during recovery in women with normal BP. Sixteen recreationally strength-trained women (age: 25.1 ± 2.9 years; height: 158.9 ± 4.1 cm; body mass: 59.5 ± 4.9 kg; body mass index: 23.5 ± 1.9 kg·m-2; baseline systolic BP median: 128 mm Hg; and baseline diastolic BP median: 78 mm Hg) were recruited. All subjects performed 6 experiments in a randomized order: (a) rest control (CON), (b) RE only (RE), (c) static-stretching exercise only (SS), (d) MM only, (e) RE immediately followed by SS (RE + SS), and (f) RE immediately followed by MM (RE + MM). RE consisted of 3 sets of bilateral bench press, back squat, front pull-down, and leg press exercises at 80% of 10RM. Static stretching and MM were applied unilaterally in 2 sets of 120 seconds to each of the quadriceps, hamstring, and calf regions. Systolic (SBP) and diastolic BP were measured before (rest) and every 10 minutes for 60 minutes following (Post 10-60) each intervention. There were significant intragroup differences for RE in Post-50 (p = 0.038; d = -2.24; ∆ = -4.0 mm Hg). Similarly, SBP intragroup differences were found for the SS protocol in Post-50 (p = 0.021; d = -2.67; ∆ = -5.0 mm Hg) and Post-60 (p = 0.008; d = -2.88; ∆ = -5.0 mm Hg). Still, SBP intragroup differences were found for the MM protocol in Post-50 (p = 0.011; d = -2.61; ∆ = -4.0 mm Hg) and Post-60 (p = 0.011; d = -2.74; ∆ = -4.0 mm Hg). Finally, a single SBP intragroup difference was found for the RE + SS protocol in Post-60 (p = 0.024; d = -3.12; ∆ = -5.0 mm Hg). Practitioners should be aware that SS and MM have the potential to influence BP responses in addition to RE or by themselves and therefore should be taken into consideration for persons who are hypertensive or hypotensive.

An Innovative Approach to Remote Electronic Health Onboarding Record Education Amid a Global Pandemic.

The COVID-19 pandemic required social and physical distancing to reduce the spread of disease. The reduction in meeting sizes made it difficult to offer traditional in-person EHR training to new and transferring employees. This paper aims to share how one nurse educator team used an innovative approach to transition traditional EHR onboarding education to synchronous remote learning during the global pandemic. Participants in the remote learning course (n = 94) were compared with those who had previously completed the traditional course (n = 110). Postcourse evaluations for each group were comparable. Remote learning participants found the technology conducive to training and reported higher scores for locating and reviewing patient information than those in the traditional course. Providing remote EHR education is comparable with traditional classroom education. Remote learning provided a safe, effective way to onboard new staff during the pandemic.

Emergency assistance in situations of abuse, neglect, and self-neglect: exploring the complexity and challenges.

Health and social care professionals are often called upon to provide emergency intervention without the adult's consent in situations of abuse, neglect, and self-neglect. Little is known about this process despite implications related to health care costs and individual rights. In this qualitative study, 17 health care professionals with experience enacting emergency legislation in BC were interviewed to better understand what leads to an emergency response and how these professionals carry out their role. Five components emerged in the provision of emergency assistance: assessing intolerable risks, assessing incapability, balancing ethical values, exploring resources, and consulting/collaborating. Attention is drawn to the significance of social location, including age, socio-economic, and Indigenous background for influencing the process, sometimes in unintended ways. The challenges in providing emergency interventions may result in social inequities and delay in providing care at times. The importance of bringing a reflexive and intersectional lens to providing interventions is highlighted.

People Are Less Susceptible to Illusion When They Use Their Hands to Communicate Rather Than Estimate.

When we use our hands to estimate the length of a stick in the Müller-Lyer illusion, we are highly susceptible to the illusion. But when we prepare to act on sticks under the same conditions, we are significantly less susceptible. Here, we asked whether people are susceptible to illusion when they use their hands not to act on objects but to describe them in spontaneous co-speech gestures or conventional sign languages of the deaf. Thirty-two English speakers and 13 American Sign Language signers used their hands to act on, estimate the length of, and describe sticks eliciting the Müller-Lyer illusion. For both gesture and sign, the magnitude of illusion in the description task was smaller than the magnitude of illusion in the estimation task and not different from the magnitude of illusion in the action task. The mechanisms responsible for producing gesture in speech and sign thus appear to operate not on percepts involved in estimation but on percepts derived from the way we act on objects.

Psychiatric mental health nurse practitioner student perceptions of integrated collaborative care.

OBJECTIVES: To explore the outcomes of threading the Patient-Centered Integrated Behavioral Health Care Principles and Tasks Checklist (AIMS Checklist) into the curricula and experiential setting. METHODS: A qualitative exploratory descriptive method with a constructivist epistemology was used to obtain in-depth student perspectives about their understanding, experiences, and process of applying Integrated Collaborative Care within the clinical setting. RESULTS: 24 Psychiatric Mental Health Nurse Practitioner Students (PMHNP) were divided into focus groups that yielded seven main themes and seven subthemes. Three of the identified themes emerged as opportunities for curriculum enhancement. CONCLUSIONS: The checklist was found to be a valuable tool in not only evaluating collaborative care but in closing the gap between didactic and clinical education in fostering student-preceptor discussion.

Small molecule inhibition of gut microbial choline trimethylamine lyase activity alters host cholesterol and bile acid metabolism.

The gut microbe-derived metabolite trimethylamine-N-oxide (TMAO) has recently been linked to cardiovascular disease (CVD) pathogenesis, prompting the development of therapeutic strategies to reduce TMAO. Previous work has shown that experimental alteration of circulating TMAO levels via dietary alterations or inhibition of the host TMAO producing enzyme flavin containing monooxygenase 3 (FMO3) is associated with reorganization of host cholesterol and bile acid metabolism in mice. In this work, we set out to understand whether recently developed nonlethal gut microbe-targeting small molecule choline trimethylamine (TMA) lyase inhibitors also alter host cholesterol and bile acid metabolism. Treatment of mice with the mechanism-based choline TMA lyase inhibitor, iodomethylcholine (IMC), increased fecal neutral sterol loss in the form of coprostanol, a bacteria metabolite of cholesterol. In parallel, IMC treatment resulted in marked reductions in the intestinal sterol transporter Niemann-pick C1-like 1 (NPC1L1) and reorganization of the gut microbial community, primarily reversing choline supplemented diet-induced changes. IMC also prevented diet-driven hepatic cholesterol accumulation, causing both upregulation of the host hepatic bile acid synthetic enzyme CYP7A1 and altering the expression of hepatic genes critical for bile acid feedback regulation. These studies suggest that the gut microbiota-driven TMAO pathway is closely linked to both microbe and host sterol and bile acid metabolism. Collectively, as gut microbe-targeting choline TMA lyase inhibitors move through the drug discovery pipeline from preclinical models to human studies, it will be important to understand how these drugs impact both microbe and host cholesterol and bile acid metabolism.NEW & NOTEWORTHY The gut microbe-dependent metabolite trimethylamine-N-oxide (TMAO) has been strongly associated with cardiovascular mortality, prompting drug discovery efforts to identify points of therapeutic intervention within the microbe host TMAO pathway. Recently, mechanism-based small molecule inhibitors of the major bacterial trimethylamine (TMA) lyase enzymes have been developed, and these drugs show efficacy as anti-atherothrombotic agents. The novel findings of this study are that small molecule TMA lyase inhibition results in beneficial reorganization of host cholesterol and bile acid metabolism. This study confirms previous observations that the gut microbial TMAO pathway is intimately linked to host cholesterol and bile acid metabolism and provides further rationale for the development of small molecule choline TMA lyase inhibitors for the treatment of cardiometabolic disorders.

Osteopontin/secreted phosphoprotein-1 behaves as a molecular brake regulating the neuroinflammatory response to chronic viral infection.

BACKGROUND: Osteopontin (OPN) as a secreted signaling protein is dramatically induced in response to cellular injury and neurodegeneration. Microglial inflammatory responses in the brain are tightly associated with the neuropathologic hallmarks of neurodegenerative disease, but understanding of the molecular mechanisms remains in several contexts poorly understood. METHODS: Micro-positron emission tomography (PET) neuroimaging using radioligands to detect increased expression of the translocator protein (TSPO) receptor in the brain is a non-invasive tool used to track neuroinflammation in living mammals. RESULTS: In humanized, chronically HIV-infected female mice in which OPN expression was knocked down with functional aptamers, uptake of TSPO radioligand DPA-713 was markedly upregulated in the cortex, olfactory bulb, basal forebrain, hypothalamus, and central grey matter compared to controls. Microglia immunoreactive for Iba-1 were more abundant in some HIV-infected mice, but overall, the differences were not significant between groups. TSPO+ microglia were readily detected by immunolabeling of post-mortem brain tissue and unexpectedly, two types of neurons also selectively stained positive for TSPO. The reactive cells were the specialized neurons of the cerebellum, Purkinje cells, and a subset of tyrosine hydroxylase-positive neurons of the substantia nigra. CONCLUSIONS: In female mice with wild-type levels of osteopontin, increased levels of TSPO ligand uptake in the brain was seen in animals with the highest levels of persistent HIV replication. In contrast, in mice with lower levels of osteopontin, the highest levels of TSPO uptake was seen, in mice with relatively low levels of persistent infection. These findings suggest that osteopontin may act as a molecular brake regulating in the brain, the inflammatory response to HIV infection.

Correction to: Osteopontin/secreted phosphoprotein-1 behaves as a molecular brake regulating the neuroinflammatory response to chronic viral infection.

An amendment to this paper has been published and can be accessed via the original article.

Beta-amyloid (Aß) uptake by PET imaging in older HIV+ and HIV- individuals.

The causes of cognitive impairment among older HIV+ individuals may overlap with causes among elderly HIV seronegative (HIV-) individuals. The objective of this study was to determine if beta-amyloid (Aß) deposition measured by [18F] AV-45 (florbetapir) positron emission tomography (PET) is increased in older HIV+ individuals compared to HIV- individuals. Forty-eight HIV+ and 25 HIV- individuals underwent [18F] AV-45 PET imaging. [18F] AV-45 binding to Aß was measured by standardized uptake value ratios (SUVR) relative to the cerebellum in 16 cortical and subcortical regions of interest. Global and regional cortical SUVRs were compared by (1) serostatus, (2) HAND stage, and (3) age decade, comparing individuals in their 50s and > 60s. There were no differences in median global cortical SUVR stratified by HIV serostatus or HAND stage. The proportion of HIV+ participants in their 50s with elevated global amyloid uptake (SUVR > 1.40) was significantly higher than the proportion in HIV- participants (67% versus 25%, p = 0.04), and selected regional SUVR values were also higher (p < 0.05) in HIV+ compared to HIV- participants in their 50s. However, these group differences were not seen in participants in their 60s. In conclusion, PET imaging found no differences in overall global Aß deposition stratified by HIV serostatus or HAND stage. Although there was some evidence of increased Aß deposition in HIV+ individuals in their 50s compared to HIV- individuals which might indicate premature aging, the most parsimonious explanation for this is the relatively small sample size in this cross-sectional cohort study.