The mechanical properties of Ti-Al₃Ti metal-intermetallic laminate (MIL) composites have been investigated with an emphasis on the effect of residual Al at the intermetallic centerline on failure mechanisms in order to ascertain the possible success or failure of using Ti-6Al-4V instead of Ti-3Al-2.5V. MIL composites consisting of alternating layers of Ti, Al, and the intermetallic phase Al₃Ti, were synthesized by reactive foil sintering in open air. Six initially identical stacks of alternating Ti-3Al-2.5V and 1100-Al foils were processed for different lengths of time, yielding specimens with different metal and intermetallic compositions. Samples were cut from each composite plate (in layer orientations parallel and perpendicular to the intended load direction) for mechanical testing in compression and four point bending, under quasi-static and high strain-rate loading conditions. Examination of the specimens and their fracture surfaces by optical and scanning electron microscopy was performed to establish a correlation between the failure mechanisms present, composite strength, and composition. Results indicated that regardless of loading direction, cracks always initiated in the intermetallic region, and crack propagation and failure were heavily influenced by the thickness of the residual aluminum layers. There is an ideal residual aluminum volume fraction that represents the amount of ductile reinforcement able to most effectively contain the oxides and impurities between intermetallic layers and thereby improve the mechanical properties of the MIL composite

CANADIAN JOURNAL OF NATIVE STUDIES: An Assessment The Canadian Journal of Native Studies, Vol. IV, Number 2, 1984, Society for the Advancement of Native Studies, Brandon University, Brandon, Manitoba, Canada. Pp. 179-388. Subscriptions: Individuals, $20.00, others $30.00. (Canadian funds inside Canada, US funds outside.) Richard T. Price The Canadian Journal of Native Studies presents readers with a microcosm of Native Studies scholarship in Canada. Much solid, scholarly work has been done in the fields of history and anthropology, and to a lesser degree in such fields as law, political science, and education. Academics have been very tentative, however, in moving beyond the comfortable niches of their own disciplines into interdisciplinary native studies research encompassing a broader scope of sources and a wider variety of methodologies. Fortunately, some scholars recently have pointed in new directions, including interdisciplinary, international, holistic and community-based ways of handling native studies research. This review of the Canadian Journal of Native Studies represents, at least symbolically, a desire for greater interaction and cooperation among American and Canadian Native Indian Studies scholars and scholarly publications. The American Indian Culture and Research Journal is to be commended for this initiative. It bodes well for the future of research in the United States, Canada and beyond. This review will describe, and critically analyze, a particular recent volume (Vol. 4, No. 2) of the Canadian Journal of Native Studies (CJNS),which contains a wide-ranging group of articles. Three main topics characterize these articles: history (Indian treaties and Indian policy administration); resource development impacts (reserve land flooding, native health and fishing); and native education (case studies using new methods). Before examining this specific edition of the CJNS, I will present a brief sketch of the journal’s history and make a status report, so that readers have a broader context for the review which follows.

Central nervous system (CNS) HIV infection is a nearly universal facet of systemic infection. Although antiretroviral therapy is generally effective in suppressing this infection and reducing its severe complications, reports of continued neurological abnormalities have questioned whether treatment developed for systemic efficacy is optimized for CNS infection. Shikuma et al. report that a 'monocyte efficacy' score based on cell culture studies and applied to antiretroviral drugs correlated with neuropsychological performance in a previously reported cohort. Although there are important questions regarding the theoretical underpinnings of both this score and its application, the findings present a novel slant on therapy.

Abstract Background A substantial prevalence of mild neurocognitive disorders has been reported in HIV, also in patients treated with combination antiretroviral therapy (cART). This includes a new disorder that has been termed asymptomatic neurocognitive impairment (ANI). Discussion ANI is identified by performance on formal neuropsychological testing that is at least 1 SD below the mean of normative scores in at least two cognitive domains out of at least five examined in patients without associated symptoms or evident functional impairment in daily living. While two tests are recommended to assess each domain, only one is required to fulfill this diagnostic criterion. Unfortunately, this definition necessitates that about 20% of the cognitively normal HIV-infected population is classified as suffering ANI. This liberal definition raises important ethical concerns and has as well diagnostic and therapeutic implications. Since neither its biological substrate, prognostic significance nor therapeutic implications are clearly established, we recommend that this diagnosis be modified or applied cautiously. Summary The diagnoses of less severe forms of neurocognitive disorders in HIV relies on the outcomes of neuropsychological testing, and a high proportion of HIV-infected patients with effective cART may be classified as neurocognitively abnormal using the current criteria. The definition of ANI is not stringent, and results in approximately 20% of the population being classified as abnormal. To us this seems an unacceptable false-positive rate.

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) begins early in systemic infection and continues throughout its untreated course. Despite a common cerebrospinal fluid inflammatory response, it is usually neurologically asymptomatic for much of this course, but can evolve in some individuals to HIV-associated dementia (HAD), a severe encephalopathy with characteristic cognitive and motor dysfunction. While widespread use of combination antiretroviral therapy (ART) has led to a marked decline in both this CNS infection and its neurologic severe consequence, HAD continues to afflict individuals presenting with advanced systemic infection in the developed world and a larger number in resource-poor settings where ART is more restricted. Additionally, milder CNS injury and dysfunction have broader prevalence, including in those treated with ART. Here we review the history and evolving nomenclature of HAD, its viral pathogenesis, clinical presentation and diagnosis, and treatment. © 2014 Elsevier B.V.

CNS infection is a nearly constant facet of systemic CNS infection and is generally well controlled by suppressive systemic antiretroviral therapy (ART). However, there are instances when HIV can be detected in the cerebrospinal fluid (CSF) despite suppression of plasma viruses below the clinical limits of measurement. We review three types of CSF viral escape: asymptomatic, neuro-symptomatic, and secondary. The first, asymptomatic CSF escape, is seemingly benign and characterized by lack of discernable neurological deterioration or subsequent CNS disease progression. Neuro-symptomatic CSF escape is an uncommon, but important, entity characterized by new or progressive CNS disease that is critical to recognize clinically because of its management implications. Finally, secondary CSF escape, which may be even more uncommon, is defined by an increase of CSF HIV replication in association with a concomitant non-HIV infection, as a consequence of the local inflammatory response. Understanding these CSF escape settings not only is important for clinical diagnosis and management but also may provide insight into the CNS HIV reservoir.

Objective

Elite controllers are a rare subset of HIV-1-infected individuals who maintain HIV-1 RNA concentrations in plasma below the lower limit of quantification of clinical assays (<20-50 copies/ml) in the absence of antiretroviral therapy. Here, we examine to what extent elite controllers also control infection of the central nervous system (CNS).

Design

We analysed paired cerebrospinal fluid (CSF) and plasma samples using a highly sensitive assay for HIV-1 RNA quantification.

Methods

We analysed 28 CSF samples and 27 concurrent plasma samples from 14 elite controllers with the highly sensitive single-copy assay (SCA) that allows for HIV-1 RNA quantification down to less than one copy of HIV-1 RNA per millilitre.

Results

Three samples were excluded because of internal standard failure. HIV-1 RNA was detected in only five of 26 CSF samples compared with 14 of 26 plasma samples (P = 0.02), with a median of 0.2 (range, 0.1-6) copies/ml in CSF compared with 0.8 (range, 0.1-189 copies/ml) in plasma (P < 0.0001).

Conclusion

HIV-1 RNA could not be detected in CSF in most elite controllers using the highly sensitive SCA, and when detected, it was at significantly lower frequencies and concentrations than in plasma. Elite controllers thus control HIV-1 in the CNS very well. Whether the infrequent and small amounts of HIV-1 RNA in the CSF reflect production from a local reservoir or virion exchange between the blood and the CSF is uncertain.

Purpose of review

The aim of this study was to examine the synaptic biomarker neurogranin in cerebrospinal fluid (CSF) in different stages of HIV infection and in relation to what is known about CSF neurogranin in other neurodegenerative diseases.

Recent findings

CSF concentrations of neurogranin are increased in Alzheimer's disease, but not in other neurodegenerative disorder such as Parkinson's disease, frontotemporal dementia, and Lewy body dementia. Adults with HIV-associated dementia have been found to have decreased levels of neurogranin in the frontal cortex, which at least to some extent, may be mediated by the proinflammatory cytokines IL-1β and IL-8. CSF neurogranin concentrations were in the same range for all groups of HIV-infected individuals and uninfected controls. This either indicates that synaptic injury is not an important part of HIV neuropathogenesis or that CSF neurogranin is not sensitive to the type of synaptic impairment present in HIV-associated neurocognitive disorders.

Human immunodeficiency virus type 1 (HIV-1) invades the central nervous system (CNS) shortly after systemic infection and can result in the subsequent development of HIV-1-associated dementia (HAD) in a subset of infected individuals. Genetically compartmentalized virus in the CNS is associated with HAD, suggesting autonomous viral replication as a factor in the disease process. We examined the source of compartmentalized HIV-1 in the CNS of subjects with HIV-1-associated neurological disease and in asymptomatic subjects who were initiating antiretroviral therapy. The heteroduplex tracking assay (HTA), targeting the variable regions of env, was used to determine which HIV-1 genetic variants in the cerebrospinal fluid (CSF) were compartmentalized and which variants were shared with the blood plasma. We then measured the viral decay kinetics of individual variants after the initiation of antiretroviral therapy. Compartmentalized HIV-1 variants in the CSF of asymptomatic subjects decayed rapidly after the initiation of antiretroviral therapy, with a mean half-life of 1.57 days. Rapid viral decay was also measured for CSF-compartmentalized variants in four HAD subjects (t(1/2) mean = 2.27 days). However, slow viral decay was measured for CSF-compartmentalized variants from an additional four subjects with neurological disease (t(1/2) range = 9.85 days to no initial decay). The slow decay detected for CSF-compartmentalized variants was not associated with poor CNS drug penetration, drug resistant virus in the CSF, or the presence of X4 virus genotypes. We found that the slow decay measured for CSF-compartmentalized variants in subjects with neurological disease was correlated with low peripheral CD4 cell count and reduced CSF pleocytosis. We propose a model in which infiltrating macrophages replace CD4(+) T cells as the primary source of productive viral replication in the CNS to maintain high viral loads in the CSF in a substantial subset of subjects with HAD.

Background

Between 0 and 48% of normal HIV-uninfected individuals score below threshold neuropsychological test scores for HIV-associated neurocognitive disorders (HAND) or are false positives. There has been little effort to understand the effect of varied interpretations of research criteria for HAND on false-positive frequencies, prevalence and analytic estimates.

Methods

The proportion of normal individuals scoring below Z score thresholds drawn from research criteria for HAND, or false-positive frequencies, was estimated in a normal Kenyan population and a simulated normal population using varied interpretations of research criteria for HAND. We calculated the impact of false-positive frequencies on prevalence estimates and statistical power.

Results

False-positive frequencies of 2-74% were observed for asymptomatic neurocognitive impairment/mild neurocognitive disorder and 0-8% for HIV-associated dementia. False-positive frequencies depended on the definition of an abnormal cognitive domain, Z score thresholds and neuropsychological battery size. Misclassification led to clinically important overestimation of prevalence and dramatic decreases in power.

Conclusions

Minimizing false-positive frequencies is critical to decrease bias in prevalence estimates and minimize reductions in power in studies of association, particularly for mild forms of HAND. We recommend changing the Z score threshold to ≤-1.5 for mild impairment, limiting analysis to 3-5 cognitive domains and using the average Z score to define an abnormal domain.