Detection and Management of Amyloid-Related Imaging Abnormalities in Patients with Alzheimer's Disease Treated with Anti-Amyloid Beta Therapy.

Amyloid-related imaging abnormalities (ARIA) are adverse events reported in Alzheimer's disease trials of anti-amyloid beta (Aß) therapies. This review summarizes the existing literature on ARIA, including bapineuzumab, gantenerumab, donanemab, lecanemab, and aducanumab studies, with regard to potential risk factors, detection, and management. The pathophysiology of ARIA is unclear, but it may be related to binding of antibodies to accumulated Aß in both the cerebral parenchyma and vasculature, resulting in loss of vessel wall integrity and increased leakage into surrounding tissues. Radiographically, ARIA-E is identified as vasogenic edema in the brain parenchyma or sulcal effusions in the leptomeninges/sulci, while ARIA-H is hemosiderin deposits presenting as microhemorrhages or superficial siderosis. ARIA tends to be transient and asymptomatic in most cases, typically occurring early in the course of treatment, with the risk decreasing later in treatment. Limited data are available on continued dosing following radiographic findings of ARIA; hence, in the event of ARIA, treatment should be continued with caution and regular monitoring. Clinical trials have implemented management approaches such as temporary suspension of treatment until symptoms or radiographic signs of ARIA have resolved or permanent discontinuation of treatment. ARIA largely resolves without concomitant treatment, and there are no systematic data on potential treatments for ARIA. Given the availability of an anti-Aß therapy, ARIA monitoring will now be implemented in routine clinical practice. The simple magnetic resonance imaging sequences used in clinical trials are likely sufficient for effective detection of cases. Increased awareness and education of ARIA among clinicians and radiologists is vital.

Novel sensitive real-time PCR for quantification of bacterial 16S rRNA genes in plasma of HIV-infected patients as a marker for microbial translocation.

We developed a real-time PCR to quantify 16S rRNA gene levels in plasma from HIV-infected patients as a marker of microbial translocation. The assay uses shrimp nuclease (SNuc) to eliminate DNA contamination, giving high sensitivity and low variability. The 16S rRNA gene levels measured in plasma from HIV patients correlated significantly with lipopolysaccharide levels.

Mucosal IL-4R antagonist HIV vaccination with SOSIP-gp140 booster can induce high-quality cytotoxic CD4+/CD8+ T cells and humoral responses in macaques.

Inducing humoral, cellular and mucosal immunity is likely to improve the effectiveness of HIV-1 vaccine strategies. Here, we tested a vaccine regimen in pigtail macaques using an intranasal (i.n.) recombinant Fowl Pox Virus (FPV)-gag pol env-IL-4R antagonist prime, intramuscular (i.m.) recombinant Modified Vaccinia Ankara Virus (MVA)-gag pol-IL-4R antagonist boost followed by an i.m SOSIP-gp140 boost. The viral vector-expressed IL-4R antagonist transiently inhibited IL-4/IL-13 signalling at the vaccination site. The SOSIP booster not only induced gp140-specific IgG, ADCC (antibody-dependent cellular cytotoxicity) and some neutralisation activity, but also bolstered the HIV-specific cellular and humoral responses. Specifically, superior sustained systemic and mucosal HIV Gag-specific poly-functional/cytotoxic CD4+ and CD8+ T cells were detected with the IL-4R antagonist adjuvanted strategy compared to the unadjuvanted control. In the systemic compartment elevated Granzyme K expression was linked to CD4+ T cells, whilst Granzyme B/TIA-1 to CD8+ T cells. In contrast, the cytotoxic marker expression by mucosal CD4+ and CD8+ T cells differed according to the mucosal compartment. This vector-based mucosal IL-4R antagonist/SOSIP booster strategy, which promotes cytotoxic mucosal CD4+ T cells at the first line of defence, and cytotoxic CD4+ and CD8+ T cells plus functional antibodies in the blood, may prove valuable in combating mucosal infection with HIV-1 and warrants further investigation.

Recovery of masked visual targets by inhibition of the masking stimulus.

Theories of visual backward masking all assume that a masked target is eliminated from the visual system. Experiments on reaction time to masked signals suggest otherwise, as does a recent demonstration that a masked target can be restored to phenomenal awareness by backward masking of the target's mask. Two experiments are reported here that substantiate the possibility of recovering a masked target, by using different stimulus materials and a more elaborate design than was employed in the first demonstration of this effect.

Endothelial characteristics of glomerular capillaries in normal, mercuric chloride-induced, and gentamicin-induced acute renal failure in the rat.

A reduction in glomerular capillary endothelial pore size and density has been reported in several models of acute renal failure. It has been suggested that these changes underlie the decrease in glomerular filtration rate and altered glomerular capillary hemodynamics measured in various experimental models of acute renal failure. We have thoroughly quantitated the surface characteristics of glomerular capillaries in control rats and in rats with either mercuric chloride-induced acute renal failure (2 mg/kg body wt) evaluated at 6 and 24 h after administration of the nephrotoxin or with gentamicin (G)1-induced acute renal failure evaluated after 8-9 d of 40 mg/kg body wt twice a day. Despite reductions in glomerular filtration rate in the experimental groups, no significant differences were observed between control (C) and any experimental group with respect to percent areas occupied by fenestrated endothelium (C = 53.6 +/- 2.7%; 6 h HgCl2 = 50.9 +/- 1.9%; 24 h HgCl2 = 53.9 +/- 5.7%; G = 56.7 +/- 2.4%), by cytoplasmic ridges (C = 31.2 +/- 1.5%; 6 h HgCl2 = 29.8 +/- 1.9%; 24 h HgCl2 = 30.6 +/- 3.1%; G = 26.5 +/- 1.5%), nonfenestrated endothelium (C = 15.5 +/- 4.0%; 6 h HgCl2 = 19.3 +/- 2.0%; 24 h HgCl2 = 15.6 +/- 4.3%; G = 16.9 +/- 2.3%), in the individual pore area expressed in square nanometers (C = 1,494 +/- 75; 6 h HgCl2 = 1,326 +/- 48; 24 h HgCl2 = 1,559 +/- 130; G = 1,340 +/- 101), or in the percentage of total pore area within fenestrated areas that were measured (C = 12.8 +/- 0.8%; 6 h HgCl2 = 11.2 +/- 0.7%; 24 h HgCl2 = 10.9 +/- 0.8%; G = 10.9 +/- 0.7%). These results provide quantitative data on the normal glomerular capillary endothelial surface characteristics and suggest that reductions of glomerular filtration rate in acute renal failure are not always associated with alterations in glomerular endothelial capillaries.

Correlation between Clinical Outcomes and Baseline CT and CT Angiographic Findings in the SWIFT PRIME Trial.

BACKGROUND AND PURPOSE: Patient selection for endovascular therapy remains a great challenge in clinic practice. We sought to determine the effect of baseline CT and angiography on outcomes in the Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) trial and to identify patients who would benefit from endovascular stroke therapy. MATERIALS AND METHODS: The primary end point was a 90-day modified Rankin Scale score of 0-2. Subgroup and classification and regression tree analysis was performed on baseline ASPECTS, site of occlusion, clot length, collateral status, and onset-to-treatment time. RESULTS: Smaller baseline infarct (n = 145) (ASPECTS 8-10) was associated with better outcomes in patients treated with thrombectomy versus IV tPA alone (66% versus 41%; rate ratio, 1.62) compared with patients with larger baseline infarcts (n = 44) (ASPECTS 6-7) (42% versus 21%; rate ratio, 1.98). The benefit of thrombectomy over IV tPA alone did not differ significantly by ASPECTS. Stratification by occlusion location also showed benefit with thrombectomy across all groups. Improved outcomes after thrombectomy occurred in patients with clot lengths of ≥8 mm (71% versus 43%; rate ratio, 1.67). Outcomes stratified by collateral status had a benefit with thrombectomy across all groups: none-fair collaterals (33% versus 0%), good collaterals (58% versus 44%), and excellent collaterals (82% versus 28%). Using a 3-level classification and regression tree analysis, we observed optimal outcomes in patients with favorable baseline ASPECTS, complete/near-complete recanalization (TICI 2b/3), and early treatment (mean mRS, 1.35 versus 3.73), while univariate and multivariate logistic regression showed significantly better results in patients with higher ASPECTS. CONCLUSIONS: While benefit was seen with endovascular therapy across multiple subgroups, the greatest response was observed in patients with a small baseline core infarct, excellent collaterals, and early treatment.

nef-deleted HIV-1 inhibits phagocytosis by monocyte-derived macrophages in vitro but not by peripheral blood monocytes in vivo.

OBJECTIVE: HIV-1 infection impairs a number of macrophage effector functions, but the mechanism is unknown. We studied the role of HIV-1 Nef in modulating phagocytosis by human monocytes and monocyte-derived macrophages (MDM). DESIGN AND METHODS: Using a flow cytometric assay, phagocytosis of Mycobacterium avium complex (MAC) by monocytes in whole blood of Sydney Blood Bank Cohort (SBBC) members infected with a nef-deleted (Delta nef) strain of HIV-1 was compared with that of monocytes from uninfected or wild-type (WT) HIV-infected subjects. The specific impact of Nef on phagocytosis by MDM was determined by either infecting cells in vitro with Delta nef strains of HIV-1 or electroporating Nef into uninfected MDM. RESULTS: MAC phagocytic capacity of monocytes from SBBC members was equivalent to that of cells from uninfected individuals (P = 0.81); it was greater than that of cells from individuals infected with WT HIV-1 (P < 0.0001), irrespective of CD4 counts and HIV viral load. In contrast, in vitro infection of MDM with either Delta nef or WT strains of HIV-1 resulted in similar levels of HIV replication and equivalent impairment of phagocytosis via Fc gamma and complement receptors. Electroporation of Nef into MDM did not alter phagocytic capacity. CONCLUSIONS: This study provides evidence demonstrating the complex indirect effect of Nef on phagocytosis by peripheral blood monocytes (infrequently infected with HIV-1) in vivo. Conversely, the fact that MDM infected with either Delta nef or WT HIV-1 in vitro (high multiplicity of infection) show comparably impaired phagocytosis, indicates that HIV-1 infection of macrophages can directly impair function, independent of Nef.

Monocytes harbour replication-competent, non-latent HIV-1 in patients on highly active antiretroviral therapy.

OBJECTIVE: To determine whether HIV-1 can be recovered from blood monocytes as well as resting, memory CD4 T lymphocytes of patients on highly active antiretroviral therapy (HAART) with undetectable plasma viraemia and whether infection is active or latent. DESIGN: Five patients with plasma HIV-1-RNA levels of less than 500 copies/ml for at least 3 months and less than 50 copies/ml at the time of sampling were initially selected, followed by an additional five patients with viral loads of less than 50 copies/ml for 3 months or more. METHODS: Monocytes were isolated from blood by plastic adherence, then further purified by a second adherence step or CD3 depletion before co-culture with CD8-depleted donor peripheral blood mononuclear cells. Virus isolates were examined for mutations conferring resistance to reverse transcriptase or protease inhibitors and for genotype. The highly purified monocytes were also analysed for the presence of proviral and unintegrated viral DNA and multiply spliced (MS) viral mRNA by polymerase chain reaction. RESULTS: Virus was recovered from monocytes of five patients. Sequencing of the recovered viruses did not reveal multiple drug resistance, and was consistent with a non-syncytium-inducing/CCR5 phenotype. Proviral DNA was detectable in monocytes from all subjects, and unintegrated HIV-1 DNA and MS RNA was found in four out of five populations examined. CONCLUSION: Recovery of replication-competent virus from some HAART patients indicates that monocytes can also harbour HIV-1. Detection of circular, viral DNA and spliced RNA, albeit at very low levels, in these cells suggests that their infection is recent and transcriptionally active rather than latent.

Human astrocytes express membrane cofactor protein (CD46), a regulator of complement activation.

Expression of membrane cofactor protein (CD46) on cultured human astrocytes was demonstrated by indirect immunofluorescence microscopy and flow cytometry following staining with a monoclonal antibody specific for CD46. Western transfer and immunoblotting detected a doublet of Mr 66,000 and 56,000. Analysis of astrocyte mRNA revealed the presence of multiple alternatively spliced transcripts encoding different extracellular regions or cytoplasmic tails of CD46. Astrocytes were also shown to express decay accelerating factor, but not the type 1 complement receptor. Upregulation of astrocyte CD46 occurred following cytomegalovirus infection. These results indicate that astrocytes express proteins involved in regulation of complement activation and protection against autologous complement.

Cross-reactivity of a normal human cell surface antigen with primate retrovirus glycoproteins.

Normal human cells express a human-specific antigen, HuLy-m5 (defined by the E4.3 monoclonal antibody), cross-reactive with determinants of the primate retroviruses, MPMV(Mason Pfizer monkey virus) and GALV (gibbon ape leukemia virus). Purified virus preparations of MPMV and GALV absorbed E4.3 antibody activity while antisera to these retroviruses blocked the binding of E4.3 antibody to human target cells. Sequential immunoprecipitation and two-dimensional gel analysis both indicated that the anti-primate retrovirus sera recognize the same molecular entity (a two-chain glycoprotein of Mr60 and 69Kd) as does the E4.3 antibody. These results suggest that normal human cells express primate retroviral proteins (most probably viral envelope glycoprotein, gp69) at the cell surface.

Routine intraoperative angioscopy in lower extremity revascularization.

The inability to see through blood remains the main obstacle to the widespread and routine use of angioscopy. Local irrigation with a balanced salt solution is presently the most widely used method to clear the blood. By applying basic principles of irrigation and using a unique, dedicated, irrigation pump, we found that routine angioscopy during lower extremity revascularization that yields consistent high-quality studies is feasible, clinically useful, and safe. Between May 1, 1987, and July 31, 1988, 136 intraoperative angioscopies were performed during 112 peripheral bypass procedures, 15 thrombectomies, 2 embolectomies, and 7 miscellaneous revascularization procedures. Mean total irrigation fluid used in the peripheral bypasses was 398 mL (range, 0 to 1400 mL). Good visual quality was obtained in more than 80% of angioscopies and the failure rate was only 1.8%. On the basis of the findings in 71 of the 136 angioscopies, 78 clinical or surgical decisions were made. No complications were directly attributable to the insertion of the angioscope or use of the pump.

Murine retroviral vector that induces long-term expression of HIV-1 envelope protein.

A retroviral vector was constructed that induces long-term expression of human immunodeficiency virus type 1 (HIV-1) rev, vpu and env genes. The vector contains the neo gene and a cytomegalovirus (CMV) immediate early promoter followed by HIV-1 sequence. When HeLa cells were infected with viral stocks derived from this vector, about 25% of the resulting G418-resistant clones expressed HIV-1 envelope protein (Env), easily detectable by Western blot analysis, metabolic labelling, and syncytium formation after co-cultivation with HeLa-CD4 cells. In most cases the level of Env expression was higher than in a T cell line (H9) chronically infected with HIV-1. Env-expressing HeLa cell lines also expressed Rev, detected by transfection with a Rev-dependent CAT gene construct, and Vpu, detected by immunoprecipitation with a Vpu-specific antiserum. The 75% of G418-resistant HeLa cell lines that did not express Env were found to contain proviruses that had undergone deletion of env sequences corresponding to a known intron; presumably these cell lines arose as a result of infection with virions derived from spliced RNAs. This vector should be useful for studying non-transient effects of HIV Env, Rev and Vpu in tissue culture, and for the production of Env- and/or Rev-expressing cell lines.

Severe mental illness and HIV-related medical and neuropsychiatric sequelae.

Medical and neuropsychiatric sequelae of HIV infection present a spectrum of diagnostic and treatment challenges to mental health clinicians. Both HIV and the many opportunistic infections that manifest in patients due to their immunocompromised state also can affect the central nervous system (CNS). Thus, mental health clinicians need to be familiar with the diagnosis and management of HIV-related medical and psychiatric complications. This article provides an overview of the CNS-related manifestations resulting from HIV disease, including HIV-related dementia, psychotic disorders, delirium, CNS opportunistic infections and tumors, systemic abnormalities, psychoactive substances, and the adverse effects of certain medical treatments. Treatment strategies for individuals with HIV disease and comorbid severe mental illness are outlined and recommendations for future research are offered.

Sex differences in verbal IQ-performance IQ discrepancies among patients with schizophrenia and normal volunteers.

Substantial verbal IQ (VIQ)-performance IQ (PIQ) discrepancies may reflect brain dysfunction. The authors examined 159 patients with schizophrenia (115 men and 44 women) or schizoaffective disorder (25 men and 19 women) and 79 normal participants (33 men and 46 women), calculated mean VIQ-PIQ discrepancy scores by sex and diagnosis, and identified persons with large VIQ-PIQ discrepancies (15-point difference in either direction). Schizophrenic/schizoaffective men had a larger mean VIQ-PIQ discrepancy than did other groups. The proportion of all patients with either VIQ > PIQ or PIQ > VIQ (17.8%) was not significantly different from that of normal participants (22.8%). However, significantly more men than women with schizophrenia exhibited a VIQ > PIQ pattern (20% vs. 3.2%). No unusual discrepancy patterns were noted among normal participants. Results were interpreted in light of theories of hemisphere dysfunction in schizophrenia.

Recovery and nonmonotone masking effects.

Recovery was produced by a homogeneous flash of light (M2). With M2 absent, correct letter report was a U-shaped curve when plotted against the interval separating the onset of a letter target and the onset of a patterned masking stimulus (M1). With the homogeneous flash of light ed to the stimulus sequence (target + M1 + M2), recovery occurred for all the shortest delays between the onsets of target and M1. Recovery peaked at a constant separation between the onsets of the target and M2, regardless, of the separation between the onsets of the target and M1. Current explanations of recovery cannot account for this result.

The effects of foveal load and visual context on peripheral letter recognition.

Peripheral letter recognition was examined by presenting subjects with a letter triad centered 7.16 degrees to the right of fixation. At the same time, a single letter was presented at the point of fixation that was either the same as one of the letters in the triad or different from any of the triad letters. On other trials, no letter was presented at the point of fixation. Results supported and extended previous foveal load research. The disruptive effect of foveal load does not depend solely on the presence or absence of a foveal stimulus. Recognition of the first letter in non-words was disrupted when a foveal letter was presented that was different from the peripheral letter. Recognition of the middle letter for both words and non-words was disrupted when a foveal letter was presented that was the same as the middle letter. A significant interaction between foveal letter and triad type was also found. No evidence was found to suggest that recognition of a peripheral letter is significantly better when that same letter is also present at the point of fixation.

Pathogenesis of replication competent retroviruses derived from mouse cells in immunosuppressed primates: implications for use of neoplastic cells as vaccine substrates.

T-cell lymphomas developed in three of 10 immunosuppressed rhesus macaques during early experiments using retroviral vectors to transfer marker genes into CD34+ bone marrow cells for subsequent transplantation in the animals. Direct PCR analyses of RNA obtained from tumour tissues from these macaques revealed the presence of several different recombinant murine leukaemia viruses (MuLV). Most prominent was a recombinant designated Mo(LTR)Ampho(env) in which the amphotropic env of the helper packaging virus was joined to a modified form of long terminal repeat (LTR) of the Moloney MuLV-derived vector that contained an additional copy of the core enhancer. This new LTR afforded enhanced replication upon the Mo(LTR)Ampho(env) MuLV in several different rhesus cell types compared with the prototype amphotropic MuLV4070A. Unexpectedly, at least two types of a mink cell focus-forming (MCF) MuLV element, arising from endogenous retroviral sequences expressed in the murine packaging cell line, were also transmitted and highly expressed in one of the macaques. Furthermore, murine virus-like VL-30 sequences were detected in the rhesus lymphomas, but these were not transcribed into RNA. The unanticipated presence of this array of MuLV-related structures in a primate gene transfer recipient highlighted the generation of recombinant retroviruses when the vector producer line produced replication competent viruses. These recombinants had an enhanced tropism and pathogenicity in the primate gene transfer recipients and frequently caused lymphomas. This primate experiment highlights the potential risk from contamination of a vaccine cell substrate with a replicating retrovirus.

Infectivity of wild-type and deleted proviral SIV DNA.

Live attenuated lentiviruses are potentially effective candidate HIV vaccines; however, delivery of these viruses in the field would be problematic. Delivery of attenuated lentiviruses as proviral DNA would be a simple means of immunization, but the efficiency of this method of delivery is not known. In this study, macaques were readily infected following inoculation of plasmid DNA encoding proviral simian immunodeficiency virus (SIVmac239), whether given i.m. (300 microg) or epidermally (15 microg), with all four animals succumbing to AIDS at a mean of 26 weeks following inoculation. Using a human skin explant model, we found that the 50% infectious dose (ID50) of proviral SIV or HIV-1 plasmid may be as low as 1 microg when delivered to skin by gold particle bombardment using a gene gun. An infectious proviral clone of SIV mac239 with a 105 bp deletion in the 3' nef/LTR overlap region was engineered (SIVsbbc delta3), analogous to the initial common nef/LTR deletion in HIV-1 strains isolated from an Australian cohort of long-term slow-progressors. Two further macaques were also readily infected with SIVsbbc delta3 after i.m. injection of 300 microg of highly purified plasmid DNA. Unexpectedly, in one macaque inoculated with SIVsbbc delta3 DNA, SIV strains isolated three to six weeks after infection had completely repaired the nef/LTR deletion with wild-type sequence, and eventually progressed to AIDS. The mechanism used to rebuild this deletion with wild-type sequence, presumably derived from an intact 5' LTR, is unclear, but possibilities include RNA read-through errors from the plasmid DNA and recombination with residual plasmid DNA at the inoculation site.

A survey of knowledge and attitudes about HIV and AIDS among medical students.

Researchers have found that a significant number of medical students harbor attitudes that have a negative impact on their willingness to care for persons who are HIV positive or have AIDS. To assess current HIV and AIDS knowledge and attitudes, the authors administered a 25-item survey tailored for medical professionals to 63 preclinical medical students. Respondents' mean score on the knowledge scale was 6.25 (SD 1.63) out of a possible score of 10. Factor analysis suggested three major groupings of medical students with regard to attitudes. The largest group had generally positive attitudes about patients with HIV and AIDS; two subgroups, however, would tend to refer such patients to another physician. One subgroup reported feeling more uncomfortable with homosexual behavior and with HIV-seropositive patients than they did with patients with other infectious diseases. This group also expressed discomfort with physically touching HIV-seropositive clients. The other group expressed discomfort with taking a patient's sexual history. Effective educational interventions must take these findings into account.

A survey of slaughter procedures used in chicken processing plants.

Information was collected on the slaughter procedures used in 12 processing plants in Australia. The processing line speed varied from 25 to 125 birds/minute; the voltage in the electrified waterbath varied from 55 to 165 V; the duration of stunning was 2.0 to 7.5 seconds and the time allowed for exsanguination was 45 to 180 seconds. As a result of the variables, some birds were dead on leaving the stunner and prior to exsanguination, while it was probable that others were not dead before entering the scald tank.