A randomised controlled trial of N-acetylcysteine in the management of anti-tuberculosis drug-induced liver injury

Background: Liver injury is the most common severe adverse effect of first-line anti-tuberculosis therapy (ATT). Nacetylcysteine (NAC) has efficacy in patients with paracetamol toxicity, and may be of benefit in liver injury due to other causes, such as ATT-induced liver injury (AT-DILI). Rechallenge of first line ATT after liver injury is usually attempted and may result in recurrence of liver injury. Alanine transaminase (ALT) is the biomarker currently used in AT-DILI diagnosis. MicroRNA-122 (miR-122) is a sensitive biomarker for liver injury due to paracetamol, but data on utility as a biomarker for ATDILI are limited. Methods: We conducted a randomized double-blind placebo-controlled trial of intravenous NAC in adult hospitalized participants with AT-DILI. Primary endpoint was time to ALT < 100 U/L; secondary endpoints included length of hospital stay and 8-week mortality. We described outcomes of ATT rechallenge following AT-DILI. We quantified miR-122 and ALT concentrations before and after infusion of NAC/placebo, and explored the effect of NAC on miR-122. Results We enrolled 102 participants with AT-DILI, 53 randomized to NAC and 49 to placebo. Mean age was 38 (SD±10) years, 58 (57%) were female and 89 (87%) were HIV positive. Median time to AL

Multicentric Castleman’s Disease

Castleman’s disease (CD) is a lymphoproliferative disorder, manifesting clinically as unicentric or multicentric disease and pathologically as hyaline vascular, plasma cell or mixed variants

Pattern of renal amyloidosis in South Africa

CITATION: Hassen, M., Bates, W. & Moosa, M. R. 2019. Pattern of renal amyloidosis in South Africa. BMC Nephrology, 20:406, doi:10.1186/s12882-019-1601-x.The original publication is available at https://bmcnephrol.biomedcentral.comBackground: Kidney disease is a serious manifestation of systemic amyloidosis and a major cause of morbidity and mortality. Tuberculosis (TB) occurs up to 27 times more commonly in human immunodeficiency virus (HIV) infected patients and is also an important cause of renal amyloid; there are however no reports of renal amyloidosis in South Africa in the HIV era. Methods: This was a retrospective record review of cases of amyloidosis diagnosed on renal biopsies at our tertiary referral hospital between January 1985 and December 2016. Results: Forty-six cases of amyloidosis were identified over the study period. The calculated biopsy prevalence was 1.38 per 100 non-transplant renal biopsies (95% Confidence Interval 1.02–1.86). AL amyloidosis was identified in 26 (57%) cases and AA in 20 (43%). The median age at presentation was 51 years and 52% of cases were female. Patients with AA amyloidosis were significantly younger compared to their AL counterparts (age 42 years vs. 58 years, p = < 0.001) and were all significantly non-white. The main clinical presentation was nephrotic syndrome (85%) and 52% of cases also had a serum creatinine value of greater than 120 μmol/L. Of the 20 cases of AA amyloidosis, 12 (60%) were associated with tuberculosis. HIV infection was noted in only two (10%) of the 20 AA cases. Median survival after diagnosis was 2 months. Conclusion: Amyloidosis is a rare cause of kidney disease and typically presents with nephrotic syndrome. A similar number of AA and AL types were observed, and outcomes are worse in cases of AA amyloid. While TB remains the major underlying disease in this type, HIV infection was infrequent in cases of AA renal amyloidosis.https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-019-1601-xPublisher's versio

Performance Improvement of Working Electrode Using Grafted Polymer Modified with SiO2 Nanoparticles

A new modified glassy carbon electrode (GCE) with grafted polymer (GP)/SiO2 nanoparticles (SiO2 NPs) were prepared using mechanical attachment method to produce a new sensor in cyclic voltammetric technique. The new working electrode GP/SiO2 NPs/GCE was characterized by a standard solution of 1 mM K4[Fe(CN)6] with 1 M K2HPO4 as an electrolyte to study the redox current peaks of FeⅡ/FeⅢ ions at different concentrations such as scan rate, pH, determination of diffusion coefficient (Df), reliability and stability of the modified GCE. It was found that the new modified electrode enhanced the redox current peaks of FeⅡ/FeⅢ from 12 μA to 20 μA and -5 μA to -15 μA for oxidation and reduction peaks in GCE, repectevely. So, the current ratio (Ipa/Ipc) for the new modified electrode was 1, and the potential peak separation (ΔEpa-c) was 100 mV, which indicated good electrochemical properties as an irreversible electrode and heterogeneous reaction. Good reliability and stability of modified GCE was obseved with low detection limit. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) analysis of the nano-deposit was also studied

Electrochemical Characterisation of the Redox Couple of Fe(II)/Fe(III) Mediated by Nano SiO2 Modified GCE Using Cyclic Voltammetry

A new modified working electrode of glassy carbon electrode with nanoparticles of SiO2 (SiO2 nanoparticles/GCE) was prepared by mechanical attachment method. The modified electrode (SiO2 nanoparticles/GCE) was characterised by electrochemical analysis using cyclic voltammetric technique to evaluate this electrode as nano-sensor. A standard solution of 1 mM K4[Fe(CN)6] with 1 M KCl as an electrolyte was used to study the redox current peaks of FeⅡ/FeⅢ ions on the modified electrode at different concentrations, scan rates, pH, determination of diffusion coefficient (Df), reliability and stability of the modified electrode. It was found the new nano-sensor (SiO2 nanoparticles/GCE) had enhancement for the oxidation and reduction current peak of FeⅡ/FeⅢ ions of about 1.29 and 1.58 μA, respectively. The current ration value of the new modified electrode was Ipa /Ipc = 1.7 with the peak separation of ∆Epa-c = 140 mV, which demonstrated that the new modified electrode acted in electrolyte as irreversible and heterogeneous reaction, had low detection limit, and enhanced the redox current peaks in acidic pH with good reliability and stability of nanoparticles on the surface of GCE

Analysis of serum microRNA-122 in a randomized controlled trial of N-acetylcysteine for treatment of antituberculosis drug-induced liver injury

AimSerum microRNA-122 (miR-122) is a novel biomarker for drug-induced liver injury, with good sensitivity in the early diagnosis of paracetamol-induced liver injury. We describe miR-122 concentrations in participants with antituberculosis drug-induced liver injury (AT-DILI). We explored the relationship between miR-122 and alanine aminotransferase (ALT) concentrations and the effect of N-acetylcysteine (NAC) on miR-122 concentrations.MethodsWe included participants from a randomized placebo-controlled trial of intravenous NAC in AT-DILI. ALT and miR-122 concentrations were quantified before and after infusion of NAC/placebo. We assessed correlations between ALT and miR-122 concentrations and described changes in ALT and miR-122 concentrations between sampling occasions.ResultsWe included 45 participants; mean age (± standard deviation) 38 (±10) years, 58% female and 91% HIV positive. The median (interquartile range) time between pre- and post-infusion biomarker specimens was 68 h (47-77 h). The median pre-infusion ALT and miR-122 concentrations were 420 U/L (238-580) and 0.58 pM (0.18-1.47), respectively. Pre-infusion ALT and miR-122 concentrations were correlated (Spearman's ρ = .54, P = .0001). Median fold-changes in ALT and miR-122 concentrations between sampling were 0.56 (0.43-0.69) and 0.75 (0.23-1.53), respectively, and were similar in the NAC and placebo groups (P = .40 and P = .68 respectively).ConclusionsmiR-122 concentrations in our participants with AT-DILI were considerably higher than previously reported in healthy volunteers and in patients on antituberculosis therapy without liver injury. We did not detect an effect of NAC on miR-122 concentrations. Further research is needed to determine the utility of miR-122 in the diagnosis and management of AT-DILI

Tunable and Linker Free Nanogaps in Core–Shell Plasmonic Nanorods for Selective and Quantitative Detection of Circulating Tumor Cells by SERS

Controlling the size, number, and shape of nanogaps in plasmonic nanostructures is of significant importance for the development of novel quantum plasmonic devices and quantitative sensing techniques such as surface-enhanced Raman scattering (SERS). Here, we introduce a new synthetic method based on coordination interactions and galvanic replacement to prepare core–shell plasmonic nanorods with tunable enclosed nanogaps. Decorating Au nanorods with Raman reporters that strongly coordinate Ag⁺ ions (e.g., 4-mercaptopyridine) afforded uniform nucleation sites to form a sacrificial Ag shell. Galvanic replacement of the Ag shell by HAuCl₄ resulted in Au–AgAu core–shell structure with a uniform intra-nanoparticle gap. The size (length and width) and morphology of the core–shell plasmonic nanorods as well as the nanogap size depend on the concentration of the coordination complexes formed between Ag⁺ ions and 4-mercaptopyridine. Moreover, encapsulating Raman reporters within the nanogaps afforded an internal standard for sensitive and quantitative SERS analysis. To test the applicability, core–shell plasmonic nanorods were functionalized with aptamers specific to circulating tumor cells such as MCF-7 (Michigan Cancer Foundation-7, breast cancer cell line). This system could selectively detect as low as 20 MCF-7 cells in a blood mimicking fluid employing SERS. The linking DNA duplex on core–shell plasmonic nanorods can also intercalate hydrophobic drug molecules such as Doxorubicin, thereby increasing the versatility of this sensing platform to include drug delivery. Our synthetic method offers the possibility of developing multifunctional SERS-active materials with a wide range of applications including biosensing, imaging, and therapy

Testing novel strategies for patients hospitalised with HIV-associated disseminated tuberculosis (NewStrat-TB): protocol for a randomised controlled trial

Background: HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalised at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. Methods: This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2 × 2 factorial design: (1) high dose rifampicin (35 mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment and (2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. Discussion: Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice. Trial registration: ClinicalTrials.gov NCT04951986. Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986