Natural Exon Skipping Sets the Stage for Exon Skipping as Therapy for Dystrophic Epidermolysis Bullosa

Contains fulltext : 214010.pdf (publisher's version ) (Open Access

Immune Responses and Pathogenesis following Experimental SARS-CoV-2 Infection in Domestic Cats

Several reports demonstrated the susceptibility of domestic cats to SARS-CoV-2 infection. Here, we describe a thorough investigation of the immune responses in cats after experimental SARS-CoV-2 inoculation, along with the characterization of infection kinetics and pathological lesions. Specific pathogen-free domestic cats (n = 12) were intranasally inoculated with SARS-CoV-2 and subsequently sacrificed on DPI (days post-inoculation) 2, 4, 7 and 14. None of the infected cats developed clinical signs. Only mild histopathologic lung changes associated with virus antigen expression were observed mainly on DPI 4 and 7. Viral RNA was present until DPI 7, predominantly in nasal and throat swabs. The infectious virus could be isolated from the nose, trachea and lungs until DPI 7. In the swab samples, no biologically relevant SARS-CoV-2 mutations were observed over time. From DPI 7 onwards, all cats developed a humoral immune response. The cellular immune responses were limited to DPI 7. Cats showed an increase in CD8+ cells, and the subsequent RNA sequence analysis of CD4+ and CD8+ subsets revealed a prominent upregulation of antiviral and inflammatory genes on DPI 2. In conclusion, infected domestic cats developed a strong antiviral response and cleared the virus within the first week after infection without overt clinical signs and relevant virus mutations.</p

Immune Responses and Pathogenesis following Experimental SARS-CoV-2 Infection in Domestic Cats

Several reports demonstrated the susceptibility of domestic cats to SARS-CoV-2 infection. Here, we describe a thorough investigation of the immune responses in cats after experimental SARS-CoV-2 inoculation, along with the characterization of infection kinetics and pathological lesions. Specific pathogen-free domestic cats ( n = 12) were intranasally inoculated with SARS-CoV-2 and subsequently sacrificed on DPI (days post-inoculation) 2, 4, 7 and 14. None of the infected cats developed clinical signs. Only mild histopathologic lung changes associated with virus antigen expression were observed mainly on DPI 4 and 7. Viral RNA was present until DPI 7, predominantly in nasal and throat swabs. The infectious virus could be isolated from the nose, trachea and lungs until DPI 7. In the swab samples, no biologically relevant SARS-CoV-2 mutations were observed over time. From DPI 7 onwards, all cats developed a humoral immune response. The cellular immune responses were limited to DPI 7. Cats showed an increase in CD8+ cells, and the subsequent RNA sequence analysis of CD4+ and CD8+ subsets revealed a prominent upregulation of antiviral and inflammatory genes on DPI 2. In conclusion, infected domestic cats developed a strong antiviral response and cleared the virus within the first week after infection without overt clinical signs and relevant virus mutations

Understanding the Emergence of Public Debt

We use a controlled laboratory experiment with and without overlapping generations to study the emergence of public debt. Public debt is chosen by popular vote, pays for public goods, and is repaid with general taxes. With a single generation, public debt is accumulated prudently, never leading to over-indebtedness. With multiple generations, public debt is accumulated rapidly as soon as the burden of debt and the risk of over-indebtedness can be shifted to future generations. Debt ceiling mechanisms do not mitigate the debt problem. With overlapping generations, political debt cycles emerge, oscillating with the age of the majority of voters

Metabolic alterations and distribution of five-carbon precursors in jasmonic acid-elicited Catharanthus roseus cell suspension cultures

Plant science

Efficacy and tolerability of brivaracetam in patients with intellectual disability and epilepsy

Patients with intellectual disability (ID) are often excluded from clinical trials, and little is known about the best approach to treat their epilepsy. Brivaracetam (BRV) is a new antiepileptic drug (AED) for adjunctive treatment in patients with focal-onset seizures with or without secondary generalization. We analyzed the efficacy and tolerability of BRV in patients with ID and epilepsy who either had or had not previously received treatment with levetiracetam (LEV). Data on efficacy and tolerability were retrospectively collected. After the initial start of BRV in our tertiary epilepsy center, we analyzed medical records at 0, 3, 6 and 12 months of follow-up. 116 patients were included (mean age = 34.9 years, 44% female). All had complete data of 3-month follow-up, 76 of 6-month follow-up, and 39 patients of 1-year follow-up. Median starting dose of BRV was 50.0 mg/day and the mean number of concomitant AEDs was 2.6. Seizure reduction and no side effects were reported in more than half of all patients. The most reported side effects were somnolence, dizziness and aggression. Retention rates for BRV were 84.4%, 75.5% and 58.1% after 3, 6 and 12 months, respectively. Seizure reduction and side effects did not differ significantly between the groups with or without previous LEV treatment. We demonstrate that BRV is effective and well tolerated in patients with epilepsy and ID, even in those where previous LEV treatment failed

Perioperative treatment and radical cystectomy for bladder cancer - A population based trend analysis of 10,338 patients in the Netherlands

Background In Europe, population-based data concerning perioperative treatment (PT) and radical cystectomy (RC) are lacking. We assessed temporal trends in PT (neoadjuvant chemotherapy [NAC], neoadjuvant radiotherapy [NAR], adjuvant chemotherapy [AC], adjuvant radiotherapy [AR]) and RC in the Netherlands and identified patients' and hospital characteristics associated with PT. Methods This nationwide, retrospective, population-based study included cTa/is, T1-4, N0-3, M0-1 bladder cancer patients from the Netherlands Cancer Registry who underwent RC with curative intent between 1995 and 2013. PT-administration over time was compared with chi-square tests. Multivariable logistic regression analyses were performed to identify characteristics associated with PT usage. The sub-groups cT2-4N0M0 and cT2-4, N0 or NX, M0 or MX were separately analysed. Results In total, 10,338 patients met inclusion criteria. Eighty-six percent did not receive PT, 7.0% received NAC (or induction chemotherapy [IC]), 3.2% NAR, 1.8% AC, and 2.1% AR. NAC usage increased from 0.6% in 1995 to 21% in 2013 (p < 0.001), application of NAR decreased from 15% to 0.4% (p < 0.001). Usage of AC and AR in 2013 was <1.5%. Comparable temporal trends were found in 6032 patients staged cT2-4N0M0. Multivariable logistic regression analysis revealed that younger age, ≥cT3, ≥cN1 and treatment in academic/teaching hospitals were associated with NAC or IC (all p < 0.05). Conclusions The increase in NAC administration in the Netherlands reflects a slow but steady adoption of evidence-based guidelines over the last two decades. Considerable variability in patients' and hospital characteristics in the likelihood of receiving NAC exists. Conversely, NAR, AR and AC are hardly administered anymore

Pathological downstaging and survival after induction chemotherapy and radical cystectomy for clinically node-positive bladder cancer-Results of a nationwide population-based study

BACKGROUND: Induction chemotherapy (IC) for clinically node-positive bladder cancer is applied without clinical evidence of improved outcome. Our objective was to compare complete pathological downstaging (pCD) and overall survival (OS) for IC versus upfront radical cystectomy (RC) in cT1-4aN1-3M0 urothelial carcinoma (UC). METHODS: This population-based study included 659 cN+ patients treated with RC between 1995 and 2013. IC was applied in 212 (32%) patients. We defined pCD as ≤(y)pT1N0 at RC. Multivariable analyses were preformed to identify independent predictors of pCD and OS. RESULTS: In cN1 and cN2-3 patients, 31% and 19% of patients proved to be pN0 at upfront RC. In cN1, pCD was achieved in 39% following IC versus 5% for upfront RC (P < 0.001). In cN2-3 UC, rates were 27% versus 3% (P < 0.001). Three-year OS for pCD and ypCD were 81% and 84%, respectively. Three-year OS rates were 66% versus 37% (cN1) and 43% versus 22% (cN2-3), again in favour of IC (P < 0.001). In multivariable analyses, IC was associated with pCD (Odds ratio, 14; 95% confidence interval [CI], 7.4-25) and a 53% decreased risk of death (Hazard ratio [HR], 0.47; 95% CI, 0.36-0.61). Indication bias and unequal distributions of factors associated with OS (e.g. patients proceeding to RC) limit interpretation of our results. CONCLUSIONS: Patients with clinical nodal involvement should not be neglected. Up to 1/4 of patients with cN+ disease had pN0 at upfront RC. Moreover, IC followed by RC for clinically node-positive UC was associated with improved pathological downstaging compared with RC alone. A potential OS benefit for IC needs to be validated in a randomised trial. TAKE HOME MESSAGE: IC followed by RC for clinically node-positive UC is associated with improved pathological downstaging compared with RC alone. A potential OS benefit for IC needs to be validated in a randomised trial