Bottom-up analysis of emergent properties of N-acetylcysteine as an adjuvant therapy for COVID-19

N-acetylcysteine (NAC) is an abundantly available antioxidant with a wide range of antidotal properties currently best studied for its use in treating acetaminophen overdose. It has a robustly established safety profile with easily tolerated side effects and presents the Food and Drug Administration's approval for use in treating acetaminophen overdose patients. It has been proven efficacious in off-label uses, such as in respiratory diseases, heart disease, cancer, human immunodeficiency virus infection, and seasonal influenza. Clinical trials have recently shown that NAC's capacity to replenish glutathione stores may significantly improve coronavirus disease 2019 (COVID-19) outcomes, especially in high risk individuals. Interestingly, individuals with glucose 6-phosphate dehydrogenase deficiency have been shown to experience even greater benefit. The same study has concluded that NAC's ability to mitigate the impact of the cytokine storm and prevent elevation of liver enzymes, C-reactive protein, and ferritin is associated with higher success rates weaning from the ventilator and return to normal function in COVID-19 patients. Considering the background knowledge of biochemistry, current uses of NAC in clinical practice, and newly acquired evidence on its potential efficacy against COVID-19, it is worthwhile to investigate further whether this agent can be used as a treatment or adjuvant for COVID-19.     

The electroencephalogram in neonatal maple syrup urine disease: a case report

Untreated maple syrup urine disease (MSUD) leads to encephalopathy in neonates and causes abnormalities on the electroencephalogram (EEG). A case is presented of MSUD with unique features consisting of a comb-like rhythm before the therapy and its disappearance with therapy is presented. This case illustrates the potential use of the EEG in the identification of this specific cause of a neonatal encephalopathy.     

Evaluation of Bacopa monniera for its Synergistic Activity with Rivastigmine in Reversing Aluminum-Induced Memory Loss and Learning Deficit in Rats

The objective of this study was to evaluate the synergistic activity of Bacopa monniera with Rivastigmine against aluminum-chloride (AlCl₃)-induced cognitive impairment in rats. Adult male Wistar rats were divided into ten groups (n = 10) and subjected to their assigned treatments for 42 days. On the 20^th day of the respective drug treatments, all the animals were trained in the Morris water maze (retention latency) and the elevated plus maze (transfer latency). After the initial training, the retention latency (RL) and the transfer latency (TL) were evaluated on the 21^st and the 42^nd days of the study. Chronic administration of AlCl₃ caused significant memory impairment associated with increased RL in the Morris water maze task and increased TL in the elevated plus maze test. Interestingly, animals treated with oral administration of B. monniera (100 and 200 mg/kg), Rivastigmine (5 mg/kg) or a combination of B. monniera (100 mg/kg) with Rivastigmine (5 mg/kg) showed significant protection against AlCl₃-induced memory impairment compared to animal treated with AlCl₃ per se. Additionally, the neuroprotective effect of B. monniera (100 and 200 mg/kg) was significantly improved when supplemented with Rivastigmine (5 mg/kg). These findings suggest that treatment with a combination of B. monniera with Rivastigmine may be highly beneficial compared to their per-se treatment.     

NAHR-mediated copy-number variants in a clinical population: Mechanistic insights into both genomic disorders and Mendelizing traits

We delineated and analyzed directly oriented paralogous low-copy repeats (DP-LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our chromosomal microarray analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically derived large data set allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR)-mediated copy-number variants (CNVs). The most commonly observed recurrent CNVs were NPHP1 duplications (233), CHRNA7 duplications (175), and 22q11.21 deletions (DiGeorge/velocardiofacial syndrome, 166). In the ∼25% of CMA cases for which parental studies were available, we identified 190 de novo recurrent CNVs. In this group, the most frequently observed events were deletions of 22q11.21 (48), 16p11.2 (autism, 34), and 7q11.23 (Williams-Beuren syndrome, 11). Several features of DP-LCRs, including length, distance between NAHR substrate elements, DNA sequence identity (fraction matching), GC content, and concentration of the homologous recombination (HR) hot spot motif 5′-CCNCCNTNNCCNC-3′, correlate with the frequencies of the recurrent CNVs events. Four novel adjacent DP-LCR-flanked and NAHR-prone regions, involving 2q12.2q13, were elucidated in association with novel genomic disorders. Our study quantitates genome architectural features responsible for NAHR-mediated genomic instability and further elucidates the role of NAHR in human disease.Copy-number variants (CNVs) are an important cause of multiple genomic disorders (Stankiewicz and Lupski 2010; Girirajan et al. 2011). One major mechanism responsible for CNV formation is nonallelic homologous recombination (NAHR) (Stankiewicz and Lupski 2002), which occurs between two paralogous low-copy repeats (LCRs) or segmental duplications (Bailey et al. 2002). Utilizing directly oriented paralogous LCR (DP-LCR) copies in cis as recombination substrates for ectopic crossovers, NAHR can lead to recurrent genomic deletions and reciprocal duplications. Recent evidence suggests a greater than twofold genome-wide enrichment for CNVs between DP-LCRs (Li et al. 2012). NAHR events in trans between LCRs on nonhomologous chromosomes can cause recurrent constitutional translocations (Giglio et al. 2002; Ou et al. 2011). For LCRs in inverted orientation, Dittwald et al. (2013) showed that 12.0% of the human genome is potentially susceptible to NAHR-mediated inversions between inverse paralogous LCRs, with 942 genes (99 of which are on the X chromosome) predicted to be disrupted secondary to such an inversion. Locus-specific studies have shown that LCR size is correlated with NAHR frequency, suggesting that ectopic synapsis precedes ectopic crossing-over (Liu et al. 2012).To date, ∼40 nonoverlapping genomic loci with deletion and/or reciprocal duplication associated with known syndromes have been identified as genomic disorders (Lupski 1998, 2009; Mefford 2009; Liu et al. 2012; Vissers and Stankiewicz 2012). Bioinformatic analyses have revealed many more regions of genomic instability in the human genome that are potentially prone to recurrent DNA rearrangements via NAHR; some of them may be pathogenic, but their phenotypic consequences remain to be elucidated.Using genome-wide bioinformatic analyses in the human genome build hg16 (July 2003), Sharp et al. (2005) predicted 130 genomic intervals flanked by DP-LCRs >10 kb in size, of >95% DNA sequence identity, with the distance between the DP-LCRs ranging from 0.05–10 Mb. Using the same parameters for bioinformatic analyses of the genome build hg19 (February 2009), Liu et al. (2012) identified 608 intervals that collapsed into 89 regions prone to DP-LCR/NAHR. Most of the differences between these data sets result from the different DP-LCRs identified in these genome builds as well as various methods for collapsing the overlapping regions.Here, we constructed bioinformatically a new genome-wide map of the DP-LCR-flanked regions in human genome build hg19 using a concept of LCR clusters. We then queried and cross-referenced our database of 25,144 high-resolution genomic analyses performed on patients referred for chromosomal microarray analysis (CMA) (Cheung et al. 2005). This approach enabled us to determine the relative frequencies in this clinical population of known recurrent genomic disorders and also to quantitate genome-wide genomic architectural features that are associated with individual locus events, to gain insights into the parameters rendering genomic instability. The frequency for ascertaining these genomic disorders varies dramatically and, as predicted previously, may reflect genome architecture and mechanism. We report the computationally determined genomic features that correlate with the empirically observed frequency of de novo recurrent rearrangements and further test, on a genome-wide scale, the “ectopic synapsis precedes ectopic crossing-over” hypothesis.     

Usefulness of superficial peroneal nerve/peroneus brevis muscle biopsy in the diagnosis of vasculitic neuropathy

Sensitivity, specificity, and diagnostic yield of the superficial peroneal nerve (SPN)/peroneus brevis muscle (PBM) biopsy in 43 patients with clinically suspected vasculitic neuropathy was studied. Biopsies were classified as “definite”, “suspicious” or “possible” in accordance with established criteria. Vasculitis was detected in 27 patients (21 with non-systemic vasculitis, and six with systemic vasculitis). In patients with “definite” vasculitis (n = 13), the sensitivity of SPN/PBM biopsy was 76.4% with 100% specificity. By including patients suspicious for vasculitis (n = 10), sensitivity increased to 85.1% but the specificity dropped to 87.5%. The overall diagnostic yield of SPN biopsy in those patients with definite vasculitis was 76.9% (10/13), and 53.8% (7/13) for muscle biopsy. The addition of muscle biopsy increased the diagnostic yield by 23%. Asymmetric nerve fiber loss, Wallerian degeneration and presence of hemosiderin were statistically significant markers of probable vasculitis. Muscle tissue was more likely to show hemosiderin (85.7%) than a nerve biopsy (71%). A combined SPN/PBM biopsy offers excellent diagnostic yield in the diagnosis of vasculitic neuropathy.     

Optic nerve and chiasm enlargement in a case of infantile Krabbe disease: quantitative comparison with 26 age-matched controls

Hypertrophy of the optic nerves and optic chiasm is described in a 5-month-old boy with infantile Krabbe disease. Optic nerve and optic chiasm hypertrophy is a rarely described feature of Krabbe disease. The areas of the prechiasmatic optic nerves and optic chiasm were measured and compared with those of 26 age-matched controls. The areas of the prechiasmatic optic nerves and optic chiasm were 132% and 53% greater than normal, respectively.