Ambulatory scintigraphic assessment of transient changes in left ventricular function: a new method for detection of silent myocardial ischaemia

Demonstration of ischaemic left ventricular dysfunction in the absence of chest pain should provide important confirmation of silent myocardial ischaemia in patients with asymptomatic ST segment changes. For this purpose, a new portable scintillation probe (VEST) similar to a miniaturized nuclear stethoscope combined with a Hotter ECG was evaluated. After standard equilibrium radionuclide angiocardiography with technetium-99m labelled red blood cells, the VEST was positioned under gamma-camera control and data were recorded from 1-12 h in 61 unselected patients. Ejection fraction (LVEF), relative changes in volumes, heart rate and ST segment changes were determined. Reproducibility of LVEF at rest (r = 0.91; variability 3.8 ± 3%, N = 19) and during exercise (r = 0.98; variability 3.2 ± 2%, N = 19) was good. In 15 asymptomatic exercise tests four different patterns of LVEF and ST segment responses were identified: (1) decrease in LVEF followed by significant ST depression (five times); (2) ST depression followed by decrease in LVEF (three times); (3) decrease in LVEF without significant ST changes (three times); and (4) ST depression without significant LVEF change (four times). In this still small series, patterns (1) to (3) corresponded to patients with documented coronary artery disease, which was not the case for pattern (4). For detection of silent ischaemia at rest, a decrease in LVEF of >5% lasting for >1 min was defined as ischaemic LV dysfunction. Using this definition, four spontaneous episodes of silent LV dysfunction could be demonstrated in two of three CCU patients with unstable angina during 160-680 min of data recordings without simultaneous ST changes. Based on this initial experience, we conclude that VEST is a reproducible method to detect transient global LV dysfunction and will be useful to confirm silent ischaemia in otherwise uncertain ST segment change

Decreasing Proportion of Recent Infections among Newly Diagnosed HIV-1 Cases in Switzerland, 2008 to 2013 Based on Line-Immunoassay-Based Algorithms.

BACKGROUND: HIV surveillance requires monitoring of new HIV diagnoses and differentiation of incident and older infections. In 2008, Switzerland implemented a system for monitoring incident HIV infections based on the results of a line immunoassay (Inno-Lia) mandatorily conducted for HIV confirmation and type differentiation (HIV-1, HIV-2) of all newly diagnosed patients. Based on this system, we assessed the proportion of incident HIV infection among newly diagnosed cases in Switzerland during 2008-2013. METHODS AND RESULTS: Inno-Lia antibody reaction patterns recorded in anonymous HIV notifications to the federal health authority were classified by 10 published algorithms into incident (up to 12 months) or older infections. Utilizing these data, annual incident infection estimates were obtained in two ways, (i) based on the diagnostic performance of the algorithms and utilizing the relationship 'incident = true incident + false incident', (ii) based on the window-periods of the algorithms and utilizing the relationship 'Prevalence = Incidence x Duration'. From 2008-2013, 3'851 HIV notifications were received. Adult HIV-1 infections amounted to 3'809 cases, and 3'636 of them (95.5%) contained Inno-Lia data. Incident infection totals calculated were similar for the performance- and window-based methods, amounting on average to 1'755 (95% confidence interval, 1588-1923) and 1'790 cases (95% CI, 1679-1900), respectively. More than half of these were among men who had sex with men. Both methods showed a continuous decline of annual incident infections 2008-2013, totaling -59.5% and -50.2%, respectively. The decline of incident infections continued even in 2012, when a 15% increase in HIV notifications had been observed. This increase was entirely due to older infections. Overall declines 2008-2013 were of similar extent among the major transmission groups. CONCLUSIONS: Inno-Lia based incident HIV-1 infection surveillance proved useful and reliable. It represents a free, additional public health benefit of the use of this relatively costly test for HIV confirmation and type differentiation

Generation of a Recombinant Gag Virus-Like-Particle Panel for the Evaluation of p24 Antigen Detection by Diagnostic HIV Tests.

BACKGROUND: Detection of HIV-1 p24 antigen permits early identification of primary HIV infection and timely intervention to limit further spread of the infection. Principally, HIV screening should equally detect all viral variants, but reagents for a standardised test evaluation are limited. Therefore, we aimed to create an inexhaustible panel of diverse HIV-1 p24 antigens. METHODS: We generated a panel of 43 recombinantly expressed virus-like particles (VLPs), containing the structural Gag proteins of HIV-1 subtypes A-H and circulating recombinant forms (CRF) CRF01_AE, CRF02_AG, CRF12_BF, CRF20_BG and group O. Eleven 4th generation antigen/antibody tests and five antigen-only tests were evaluated for their ability to detect VLPs diluted in human plasma to p24 concentrations equivalent to 50, 10 and 2 IU/ml of the WHO p24 standard. Three tests were also evaluated for their ability to detect p24 after heat-denaturation for immune-complex disruption, a pre-requisite for ultrasensitive p24 detection. RESULTS: Our VLP panel exhibited an average intra-clade p24 diversity of 6.7%. Among the 4th generation tests, the Abbott Architect and Siemens Enzygnost Integral 4 had the highest sensitivity of 97.7% and 93%, respectively. Alere Determine Combo and BioRad Access were least sensitive with 10.1% and 40.3%, respectively. Antigen-only tests were slightly more sensitive than combination tests. Almost all tests detected the WHO HIV-1 p24 standard at a concentration of 2 IU/ml, but their ability to detect this input for different subtypes varied greatly. Heat-treatment lowered overall detectability of HIV-1 p24 in two of the three tests, but only few VLPs had a more than 3-fold loss in p24 detection. CONCLUSIONS: The HIV-1 Gag subtype panel has a broad diversity and proved useful for a standardised evaluation of the detection limit and breadth of subtype detection of p24 antigen-detecting tests. Several tests exhibited problems, particularly with non-B subtypes

A step-economical multicomponent synthesis of 3D-shaped aza-diketopiperazines and their drug-like chemical space analysis

A rapid and atom economical multicomponent synthesis of complex aza-diketopiperazines (aza-DKPs) driven by Rh(I)-catalyzed hydroformylation of alkenylsemicarbazides is described. Combined with catalytic amounts of acid and the presence of nucleophilic species, this unprecedented multicomponent reaction (MCR) enabled the formation of six bonds and a controlled stereocenter from simple substrates. The efficacy of the strategy was demonstrated with a series of various allyl-substituted semicarbazides and nucleophiles leading to the preparation of 3D-shaped bicyclic aza-DKPs. Moreover, an analysis of their 3D molecular descriptors and “drug-likeness” properties highlights not only their originality in the chemical space of aza-heterocycles but also their great potential for medicinal chemistry

High prevalence of anti-C1q antibodies in biopsy-proven active lupus nephritis

BACKGROUND: Anti-C1q antibodies (anti-C1q) have been shown to correlate positively with systemic lupus erythematosus (SLE) nephritis. Several clinical studies indicated a high negative predictive value, suggesting that active lupus nephritis is rarely seen in patients with no anti-C1q. However, the true prevalence of anti-C1q at the time of active lupus nephritis has not been well established. The aim of this study was to determine prospectively the prevalence of anti-C1q in proven active lupus nephritis at the time of the renal biopsy. METHODS: In this prospective multi-centre study, we investigated adult SLE patients undergoing renal biopsy for suspected active lupus nephritis. Serum samples were taken at the time of the biopsy and analysed for the presence of anti-C1q in a standardized way. The activity of lupus nephritis was classified according to the renal histology. Biopsies were also analysed for the presence of glomerular IgG, C1q and C3 deposition. RESULTS: A total of 38 patients fulfilling at least 4/11 American College of Rheumatology (ACR) criteria for the diagnosis of SLE were included. Out of this, 36 patients had proliferative (class II, III or IV) and two had class V lupus nephritis. All but one patient with proliferative lupus nephritis were positive for anti-C1q (97.2%) compared with the 35% of control SLE patients with inactive lupus nephritis and 25% of SLE patients without lupus nephritis ever. All patients were positive for glomerular C1q (36/36) and 37/38 patients had glomerular IgG deposits. Anti-C1q strongly decreased during successful treatment. CONCLUSIONS: Anti-C1q have a very high prevalence in biopsy-proven active lupus nephritis, thus a negative test result almost excludes active nephritis. The data support the hypothesis of a pathogenic role of anti-C1q in lupus nephritis

Anti-hLAMP2-antibodies and dual positivity for anti-GBM and MPO-ANCA in a patient with relapsing pulmonary-renal syndrome

Background Pulmonary-renal syndrome associated with anti-glomerular basement membrane (GBM) antibodies, also known as Goodpasture's syndrome, is a rare but acute and life-threatening condition. One third of patients presenting as anti-GBM antibody positive pulmonary-renal syndrome or rapidly progressive glomerulonephritis are also tested positive for anti-neutrophil cytoplasmic antibodies (ANCA). Whilst anti-GBM disease is considered a non-relapsing condition, the long-term course of double-positive patients is less predictable. Case Presentation We report a patient with such dual positivity, who presented with pulmonary hemorrhage, crescentic glomerulonephritis and membranous nephropathy. Plasmapheresis in combination with immunosuppresive therapy led to a rapid remission but the disease relapsed after two years. The serum of the patient was tested positive for antibodies to human lysosomal membrane protein 2 (hLAMP2), a novel autoantigen in patients with active small-vessel vasculitis (SVV). The anti-hLAMP2 antibody levels correlated positively with clinical disease activity in this patient. Conclusion We hypothesize that this antibody may indicate a clinical course similar to ANCA-associated vasculitis in double-positive patients. However, this needs to be confirmed on comprehensive patient cohorts

High specificity of line-immunoassay based algorithms for recent HIV-1 infection independent of viral subtype and stage of disease

ABSTRACT: BACKGROUND: Serologic testing algorithms for recent HIV seroconversion (STARHS) provide important information for HIV surveillance. We have shown that a patient's antibody reaction in a confirmatory line immunoassay (INNO-LIATM HIV I/II Score, Innogenetics) provides information on the duration of infection. Here, we sought to further investigate the diagnostic specificity of various Inno-Lia algorithms and to identify factors affecting it. METHODS: Plasma samples of 714 selected patients of the Swiss HIV Cohort Study infected for longer than 12 months and representing all viral clades and stages of chronic HIV-1 infection were tested blindly by Inno-Lia and classified as either incident (up to 12 m) or older infection by 24 different algorithms. Of the total, 524 patients received HAART, 308 had HIV-1 RNA below 50 copies/mL, and 620 were infected by a HIV-1 non-B clade. Using logistic regression analysis we evaluated factors that might affect the specificity of these algorithms. RESULTS: HIV-1 RNA <50 copies/mL was associated with significantly lower reactivity to all five HIV-1 antigens of the Inno-Lia and impaired specificity of most algorithms. Among 412 patients either untreated or with HIV-1 RNA ≥50 copies/mL despite HAART, the median specificity of the algorithms was 96.5% (range 92.0-100%). The only factor that significantly promoted false-incident results in this group was age, with false-incident results increasing by a few percent per additional year. HIV-1 clade, HIV-1 RNA, CD4 percentage, sex, disease stage, and testing modalities exhibited no significance. Results were similar among 190 untreated patients. CONCLUSIONS: The specificity of most Inno-Lia algorithms was high and not affected by HIV-1 variability, advanced disease and other factors promoting false-recent results in other STARHS. Specificity should be good in any group of untreated HIV-1 patients

Humanized Mice Recapitulate Key Features of HIV-1 Infection: A Novel Concept Using Long-Acting Anti-Retroviral Drugs for Treating HIV-1

BACKGROUND: Humanized mice generate a lymphoid system of human origin subsequent to transplantation of human CD34+ cells and thus are highly susceptible to HIV infection. Here we examined the efficacy of antiretroviral treatment (ART) when added to food pellets, and of long-acting (LA) antiretroviral compounds, either as monotherapy or in combination. These studies shall be inspiring for establishing a gold standard of ART, which is easy to administer and well supported by the mice, and for subsequent studies such as latency. Furthermore, they should disclose whether viral breakthrough and emergence of resistance occurs similar as in HIV-infected patients when ART is insufficient. METHODS/PRINCIPAL FINDINGS: NOD/shi-scid/γ(c)null (NOG) mice were used in all experimentations. We first performed pharmacokinetic studies of the drugs used, either added to food pellets (AZT, TDF, 3TC, RTV) or in a LA formulation that permitted once weekly subcutaneous administration (TMC278: non-nucleoside reverse transcriptase inhibitor, TMC181: protease inhibitor). A combination of 3TC, TDF and TMC278-LA or 3TC, TDF, TMC278-LA and TMC181-LA suppressed the viral load to undetectable levels in 15/19 (79%) and 14/14 (100%) mice, respectively. In successfully treated mice, subsequent monotherapy with TMC278-LA resulted in viral breakthrough; in contrast, the two LA compounds together prevented viral breakthrough. Resistance mutations matched the mutations most commonly observed in HIV patients failing therapy. Importantly, viral rebound after interruption of ART, presence of HIV DNA in successfully treated mice and in vitro reactivation of early HIV transcripts point to an existing latent HIV reservoir. CONCLUSIONS/SIGNIFICANCE: This report is a unique description of multiple aspects of HIV infection in humanized mice that comprised efficacy testing of various treatment regimens, including LA compounds, resistance mutation analysis as well as viral rebound after treatment interruption. Humanized mice will be highly valuable for exploring the antiviral potency of new compounds or compounds targeting the latent HIV reservoir

Ageing with HIV: medication use and risk for potential drug-drug interactions

Objectives To compare the use of co-medication, the potential drug-drug interactions (PDDIs) and the effect on antiretroviral therapy (ART) tolerability and efficacy in HIV-infected individuals according to age, ≥50 years or <50 years. Methods All ART-treated participants were prospectively included once during a follow-up visit of the Swiss HIV Cohort Study. Information on any current medication was obtained by participant self-report and medical prescription history. The complete treatment was subsequently screened for PDDIs using a customized version of the Liverpool drug interaction database. Results Drug prescriptions were analysed for 1497 HIV-infected individuals: 477 age ≥50 and 1020 age <50. Older patients were more likely to receive one or more co-medications compared with younger patients (82% versus 61%; P < 0.001) and thus had more frequent PDDIs (51% versus 35%; P < 0.001). Furthermore, older patients tended to use a higher number of co-medications and certain therapeutic drug classes more often, such as cardiovascular drugs (53% versus 19%; P < 0.001), gastrointestinal medications (10% versus 6%; P = 0.004) and hormonal agents (6% versus 3%; P = 0.04). PDDIs with ART occurred mainly with cardiovascular drugs (27%), CNS agents (22%) and methadone (6%) in older patients and with CNS agents (27%), methadone (15%) and cardiovascular drugs (11%) in younger patients. The response to ART did not differ between the two groups. Conclusions The risk for PDDIs with ART increased in older patients who take more drugs than their younger HIV-infected counterparts. However, medication use in older and younger patients did not differ in terms of effect on antiretroviral tolerability and respons

The Interplay Between Host Genetic Variation, Viral Replication, and Microbial Translocation in Untreated HIV-Infected Individuals

Systemic immune activation, a major determinant of human immunodeficiency virus (HIV) disease progression, is the result of a complex interplay between viral replication, dysregulation of the immune system, and microbial translocation due to gut mucosal damage. Although human genetic variants influencing HIV load have been identified, it is unknown how much the host genetic background contributes to interindividual differences in other determinants of HIV pathogenesis such as gut damage and microbial translocation. Using samples and data from 717 untreated participants in the Swiss HIV Cohort Study and a genome-wide association study design, we searched for human genetic determinants of plasma levels of intestinal fatty acid-binding protein (I-FABP/FABP2), a marker of gut damage, and of soluble CD14 (sCD14), a marker of lipopolysaccharide bioactivity and microbial translocation. We also assessed the correlations between HIV load, sCD14, and I-FABP. Although we found no genome-wide significant determinant of the tested plasma markers, we observed strong associations between sCD14 and both HIV load and I-FABP, shedding new light on the relationships between processes that drive progression of untreated HIV infectio