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The primordial terminal structures (telomeres) of linear chromosomes in eukaryotic nuclei were derived from selfish elements, which caused the linearization of the ancestral circular genome and helped in solving the emerged problems. The molecular fossils of such elements were identified in phylogenetically distant genomes and were shown to generate terminal arrays of tandem repeats.

Background Cryptococcal meningoencephalitis (CM) is a major cause of mortality in immunosuppressed patients and previously healthy individuals. In the latter, a post-infectious inflammatory response syndrome (PIIRS) is associated with poor clinical response despite antifungal therapy and negative cerebrospinal fluid (CSF) cultures. Data on effective treatment are limited. Methods Between March 2015 and March 2020, 15 consecutive previously healthy patients with CM and PIIRS were treated with adjunctive pulse corticosteroid taper therapy (PCT) consisting of intravenous methylprednisolone 1 gm daily for 1 week followed by oral prednisone 1 mg/kg/day, tapered based on clinical and radiological response plus oral fluconazole. Montreal cognitive assessments (MOCA), Karnofsky performance scores, magnetic resonance imaging (MRI) brain scanning, ophthalmic and audiologic exams, and CSF parameters including cellular and soluble immune responses were compared at PIIRS diagnosis and after methylprednisolone completion. Results The median time from antifungal treatment to steroid initiation was 6 weeks. The most common symptoms at PIIRS diagnosis were altered mental status and vision changes. All patients demonstrated significant improvements in MOCA and Karnofsky scores at 1 month (P  < .0003), which was accompanied by improvements in CSF glucose, white blood cell (WBC) count, protein, cellular and soluble inflammatory markers 1 week after receiving corticosteroids (CS) (P  < .003). All patients with papilledema and visual field deficits also exhibited improvement (P  < .0005). Five out of 7 patients who underwent audiological testing demonstrated hearing improvement. Brain MRI showed significant improvement of radiological findings (P  = .001). CSF cultures remained negative. Conclusions PCT in this small cohort of PIIRS was associated with improvements in CM-related complications with minimal toxicity in the acute setting. [ABSTRACT FROM AUTHOR]

Background: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) are approved for the treatment of disease activity and are effective in reducing relapses and new magnetic resonance imaging (MRI) lesions. However, disease activity generally subsides with time, and age-dependent changes in DMT efficacy are not well-established. We aimed to investigate whether age impacts the efficacy of DMTs in treating disease activity in patients with relapsing–remitting MS (RRMS). Methods: DMT efficacy related to age was assessed through a meta-analysis of clinical trials that evaluated the efficacy of DMTs in RRMS patients as measured by reductions in the annualized relapse rate (ARR), new T2 lesions, and gadolinium-enhanced lesions on MRI. Using the mean baseline patient age from each trial, a weighted linear regression was fitted to determine whether age was associated with treatment efficacy on a group level. Results: Group-level data from a total of 28,082 patients from 26 trials of 14 different DMTs were included in the meta-analysis. There were no statistically significant associations between age and reductions in ARR, new T2 lesions, and gadolinium-enhanced lesions of the treatment group compared with placebo. Conclusion: DMTs for RRMS show efficacy in treating disease activity independent of age as demonstrated by group-level data from DMT clinical trials. Nevertheless, clinical trials select for patients with baseline disease activity regardless of age, thereby not representing real-world patients with RRMS, where disease activity declines with age. [ABSTRACT FROM AUTHOR]

No genetic modifiers of multiple sclerosis (MS) severity have been independently validated, leading to a lack of insight into genetic determinants of the rate of disability progression. We investigated genetic modifiers of MS severity in prospectively acquired training (N = 205) and validation (N = 94) cohorts, using the following advances: (1) We focused on 113 genetic variants previously identified as related to MS severity; (2) We used a novel, sensitive outcome: MS Disease Severity Scale (MS‐DSS); (3) Instead of validating individual alleles, we used a machine learning technique (random forest) that captures linear and complex nonlinear effects between alleles to derive a single Genetic Model of MS Severity (GeM‐MSS). The GeM‐MSS consists of 19 variants located in vicinity of 12 genes implicated in regulating cytotoxicity of immune cells, complement activation, neuronal functions, and fibrosis. GeM‐MSS correlates with MS‐DSS (r = 0.214; p = 0.043) in a validation cohort that was not used in the modeling steps. The recognized biology identifies novel therapeutic targets for inhibiting MS disability progression. [ABSTRACT FROM AUTHOR]