Neuroimaging of Vessel Amyloid in Alzheimer's Disease a , b

Despite extensive recent advances in understanding Alzheimer's disease (AD) we are unable to noninvasively establish a definite diagnosis during life and cannot monitor the cerebral deposition of amyloid Β protein (A/Β) in living patients. We evaluated the use of 10H3, a monoclonal antibody Fab targeting AΒ protein 1-28 labeled with Tc-99m. Six subjects with probable AD were studied using single-photon emission computed tomography (SPECT) at times from 0–24 hours following injection. Curves of radioactivity in blood demonstrate a half-life of the injected Fab of 2–3 hours. Images show uptake around the head in the scalp or bone marrow in all subjects. There is no evidence of cerebral uptake of the antibody. Scalp biopsies in all six patients demonstrate diffuse staining with 10H3 of the scalp, a pattern indistinguishable from that found in controls. Evidence of amyloid deposition in the scalp in AD is not seen with other anti-AΒ antibodies, suggesting that 10H3 is cross-reacting with another protein. Further studies with anti-AΒ antibodies will require longer-lived radionuclides to detect cerebral uptake at later tunes after injection to allow for complete clearance from the blood. Afternately, imaging using labeled AΒ itself may provide a means for noninvasive targeting of cerebral amyloid.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73674/1/j.1749-6632.1997.tb48475.x.pd

Carbonic anhydrase inhibitors limit complications in X-linked retinoschisis

PurposeCarbonic anhydrase inhibitors (CAIs) reduce macular schisis in patients with X-linked retinoschisis (XLRS). The purpose of this study was to determine if CAIs reduce the incidence of complications from XLRS, including macular atrophy, retinal tears, and retinal detachment (RD), the most common causes of vision loss in patients with XLRS.MethodsFor this retrospective interventional case series, a chart review of patients examined at Cincinnati Children’s Hospital Medical Center [CCHMC] and Cincinnati Eye Institute [CEI] between 1/1/2015 and 1/16/2023 was performed. Male patients were included based on genetically-confirmed RS1 or typical clinical presentation with known family history of XLRS with at least two follow-up visits.ResultsTwenty-eight patients (56 eyes) with XLRS were included. There were 10 RS1 variants among the 21 genotyped patients. Median age at clinical diagnosis was 10.4 years old (range: 0.4–55.7 years) with median follow-up time of 4.7 years (range: 0.2–38.3 years). Median presenting Snellen visual acuity was 20/60 (logMAR 0.48, range: 0.18–3). In 26 eyes of 15 patients treated with CAIs, median CST pre-treatment was 416 microns (range: 198–701 microns), and median percentage decrease in CST on treatment was 21.8% (range: 0–74.5%) from highest pre-treatment CST. Reduction in CST with CAI use was statistically significant (p = 0.02), but not logMAR VA (p = 0.64). There was no significant difference in CST between patients treated with topical vs. oral CAI (p = 0.95) or between patients with partial or complete CAI adherence (p = 0.60). Ten eyes of seven patients had an RD requiring surgical intervention. No treated eyes developed new macular atrophy, peripheral retinoschisis, retinal tears, or RD; two eyes on topical CAIs had spontaneous resolution of bullous peripheral retinoschisis.ConclusionDuring the follow-up period, patients taking CAIs reduced macular schisis and did not experience new complications of macular atrophy, retinal tears, or RD. This is a relatively large cohort with long-term follow-up periods for patients with XLRS. Reduced macular schisis may not require perfect adherence with CAIs. A large, prospective, randomized, controlled clinical trial is needed to determine the potential of CAIs to improve visual function, reduce retinoschisis, and prevent RD

Hybrid Gene Origination Creates Human-Virus Chimeric Proteins during Infection

RNA viruses are a major human health threat. The life cycles of many highly pathogenic RNA viruses like influ-enza A virus (IAV) and Lassa virus depends on host mRNA, because viral polymerases cleave 50-m7G-cappedhost transcripts to prime viral mRNA synthesis (‘‘cap-snatching’’). We hypothesized that start codons withincap-snatched host transcripts could generate chimeric human-viral mRNAs with coding potential. We reportthe existence of this mechanism of gene origination, which we named ‘‘start-snatching.’’ Depending on thereading frame, start-snatching allows the translation of host and viral ‘‘untranslated regions’’ (UTRs) to createN-terminally extended viral proteins or entirely novel polypeptides by genetic overprinting. We show thatboth types of chimeric proteins are made in IAV-infected cells, generate T cell responses, and contributeto virulence. Our results indicate that during infection with IAV, and likely a multitude of other human, animaland plant viruses, a host-dependent mechanism allows the genesis of hybrid genes

Hybrid Gene Origination Creates Human-Virus Chimeric Proteins during Infection

RNA viruses are a major human health threat. The life cycles of many highly pathogenic RNA viruses like influenza A virus (IAV) and Lassa virus depends on host mRNA, because viral polymerases cleave 5'-m7G-capped host transcripts to prime viral mRNA synthesis ("cap-snatching"). We hypothesized that start codons within cap-snatched host transcripts could generate chimeric human-viral mRNAs with coding potential. We report the existence of this mechanism of gene origination, which we named "start-snatching." Depending on the reading frame, start-snatching allows the translation of host and viral "untranslated regions" (UTRs) to create N-terminally extended viral proteins or entirely novel polypeptides by genetic overprinting. We show that both types of chimeric proteins are made in IAV-infected cells, generate T cell responses, and contribute to virulence. Our results indicate that during infection with IAV, and likely a multitude of other human, animal and plant viruses, a host-dependent mechanism allows the genesis of hybrid genes

TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans

TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation.

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans