Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Complement proteins and activation products have been found associated with neuropathology in Alzheimer's disease (AD). Recently, a C5a receptor antagonist was shown to suppress neuropathology in two murine models of AD, Tg2576 and 3xTg. Previously, a genetic deficiency of C1q in the Tg2576 mouse model showed an accumulation of fibrillar plaques similar to the complement sufficient Tg2576, but reactive glia were significantly decreased and neuronal integrity was improved suggesting detrimental consequences for complement activation in AD. The goal of this study was to define the role of the classical complement activation pathway in the progression of pathology in the 3xTg mouse that develops tangles in addition to fibrillar plaques (more closely reflecting human AD pathology) and to assess the influence of complement in a model of AD with a higher level of complement hemolytic activity.</p> <p>Methods</p> <p>3xTg mice deficient in C1q (3xTgQ-/-) were generated, and both 3xTg and 3xTgQ-/- were backcrossed to the BUB mouse strain which has higher in vitro hemolytic complement activity. Mice were aged and perfused, and brain sections stained for pathological markers or analyzed for proinflammatory marker expression.</p> <p>Results</p> <p>3xTgQ-/- mice showed similar amounts of fibrillar amyloid, reactive glia and hyperphosphorylated tau as the C1q-sufficient 3xTg at the ages analyzed. However, 3xTg and 3xTgQ-/- on the BUB background developed pathology earlier than on the original 3xTg background, although the presence of C1q had no effect on neuropathological and pro-inflammatory markers. In contrast to that seen in other transgenic models of AD, C1q, C4 and C3 immunoreactivity was undetectable on the plaques of 3xTg in any background, although C3 was associated with reactive astrocytes surrounding the plaques. Importantly, properdin a component of the alternative complement pathway was associated with plaques in all models.</p> <p>Conclusions</p> <p>In contrast to previously investigated transgenic models of AD, development of neuropathology in 3xTg mice, which progresses much slower than other murine models, may not be influenced by fibrillar amyloid mediated activation of the classical complement pathway, suggesting that the alternative complement pathway activation or a C3-independent cleavage of C5 could account for the detrimental effects in these mice that are prevented by the C5a receptor antagonist. Furthermore, the paucity of complement activation may be a factor in the slower kinetics of progression of pathology in the 3xTg model of this disease.</p

Radial Columns in Cortical Architecture: It Is the Composition That Counts

The function of any brain structure depends on its neuronal composition and on the pattern of its extrinsic and intrinsic excitatory and inhibitory synaptic connectivity. In this issue of Cerebral Cortex, 3 related papers provide the most comprehensive analysis to date of the cellular and synaptic relationships of a standard cortical column in the somatosensory cortex of the Wistar rat. It is hoped that understanding normal composition of this archetypical cortical column may help to explain its functional operations, expose subtle pathological changes that could cause abnormal sensory and cognitive functions, and provide insight into evolution of the cerebral cortex

Survey of the quality of experimental design, statistical analysis and reporting of research using animals

For scientific, ethical and economic reasons, experiments involving animals should be appropriately designed, correctly analysed and transparently reported. This increases the scientific validity of the results, and maximises the knowledge gained from each experiment. A minimum amount of relevant information must be included in scientific publications to ensure that the methods and results of a study can be reviewed, analysed and repeated. Omitting essential information can raise scientific and ethical concerns. We report the findings of a systematic survey of reporting, experimental design and statistical analysis in published biomedical research using laboratory animals. Medline and EMBASE were searched for studies reporting research on live rats, mice and non-human primates carried out in UK and US publicly funded research establishments. Detailed information was collected from 271 publications, about the objective or hypothesis of the study, the number, sex, age and/or weight of animals used, and experimental and statistical methods. Only 59% of the studies stated the hypothesis or objective of the study and the number and characteristics of the animals used. Appropriate and efficient experimental design is a critical component of high-quality science. Most of the papers surveyed did not use randomisation (87%) or blinding (86%), to reduce bias in animal selection and outcome assessment. Only 70% of the publications that used statistical methods described their methods and presented the results with a measure of error or variability. This survey has identified a number of issues that need to be addressed in order to improve experimental design and reporting in publications describing research using animals. Scientific publication is a powerful and important source of information; the authors of scientific publications therefore have a responsibility to describe their methods and results comprehensively, accurately and transparently, and peer reviewers and journal editors share the responsibility to ensure that published studies fulfil these criteria

Theoretical Risk of Genetic Reassortment Should Not Impede Development of Live, Attenuated Rift Valley Fever (RVF) Vaccines Commentary on the Draft WHO RVF Target Product Profile

In November 2019, The World Health Organization (WHO) issued a draft set of Target Product Profiles (TPPs) describing optimal and minimally acceptable targets for vaccines against Rift Valley fever (RVF), a Phlebovirus with a three segmented genome, in both humans and ruminants. The TPPs contained rigid requirements to protect against genomic reassortment of live, attenuated vaccines (LAVs) with wild-type RVF virus (RVFV), which place undue constraints on development and regulatory approval of LAVs. We review the current LAVs in use and in development, and conclude that there is no evidence that reassortment between LAVs and wild-type RVFV has occurred during field use, that such a reassortment event if it occurred would have no untoward consequence, and that the TPPs should be revised to provide a more balanced assessment of the benefits versus the theoretical risks of reassortment

Epidemic space

The aim of this article is to highlight the importance of 'spatiality' in understanding the materialization of risk society and cultivation of risk sensibilities. More specifically it provides a cultural analysis of pathogen virulence (as a social phenomenon) by means of tracing and mapping the spatial flows that operate in the uncharted zones between the microphysics of infection and the macrophysics of epidemics. It will be argued that epidemic space consists of three types of forces: the vector, the index and the vortex. It will draw on Latour's Actor Network Theory to argue that epidemic space is geared towards instability when the vortex (of expanding associations and concerns) displaces the index (of finding a single cause)

Risk-Stratified Screening for Colorectal Cancer Using Genetic and Environmental Risk Factors:A Cost-Effectiveness Analysis Based on Real-World Data

Background &amp; Aims: Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death. Methods: Risk predictions for CRC and competing causes of death from a large community-based cohort were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40–60 years), end age (70–85 years), and screening interval (5–15 years). The outcomes included personalized screening ages and intervals and cost-effectiveness compared with uniform colonoscopy screening (ages 45–75, every 10 years). Key assumptions were varied in sensitivity analyses. Results: Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every 5 years from ages 40 to 85 for high-risk individuals. Nevertheless, on a population level, risk-stratified screening would increase net quality-adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening or reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test. Conclusions: Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small.</p

The Updated Zwicky Catalog (UZC)

The Zwicky Catalog of galaxies (ZC), with m_Zw<=15.5mag, has been the basis for the Center for Astrophysics (CfA) redshift surveys. To date, analyses of the ZC and redshift surveys based on it have relied on heterogeneous sets of galaxy coordinates and redshifts. Here we correct some of the inadequacies of previous catalogs by providing: (1) coordinates with <~2 arcsec errors for all of the Nuzc catalog galaxies, (2) homogeneously estimated redshifts for the majority (98%) of the data taken at the CfA (14,632 spectra), and (3) an estimate of the remaining "blunder" rate for both the CfA redshifts and for those compiled from the literature. For the reanalyzed CfA data we include a calibrated, uniformly determined error and an indication of the presence of emission lines in each spectrum. We provide redshifts for 7,257 galaxies in the CfA2 redshift survey not previously published; for another 5,625 CfA redshifts we list the remeasured or uniformly re-reduced value. Among our new measurements, Nmul are members of UZC "multiplets" associated with the original Zwicky catalog position in the coordinate range where the catalog is 98% complete. These multiplets provide new candidates for examination of tidal interactions among galaxies. All of the new redshifts correspond to UZC galaxies with properties recorded in the CfA redshift compilation known as ZCAT. About 1,000 of our new measurements were motivated either by inadequate signal-to-noise in the original spectrum or by an ambiguous identification of the galaxy associated with a ZCAT redshift. The redshift catalog we include here is ~96% complete to m_Zw<=15.5, and ~98% complete (12,925 galaxies out of a total of 13,150) for the RA(1950) ranges [20h--4h] and [8h--17h] and DEC(1950) range [-2.5d--50d]. (abridged)Comment: 34 pp, 7 figs, PASP 1999, 111, 43

Consolidated standards of reporting trials (CONSORT) and the completeness of reporting of randomised controlled trials (RCTs) published inmedical journals (Review)

Background: An overwhelming body of evidence stating that the completeness of reporting of randomised controlled trials (RCTs) is not optimal has accrued over time. In the mid-1990s, in response to these concerns, an international group of clinical trialists, statisticians, epidemiologists, and biomedical journal editors developed the CONsolidated Standards Of Reporting Trials (CONSORT) Statement. The CONSORT Statement, most recently updated in March 2010, is an evidence-based minimum set of recommendations including a checklist and flow diagram for reporting RCTs and is intended to facilitate the complete and transparent reporting of trials and aid their critical appraisal and interpretation. In 2006, a systematic review of eight studies evaluating the “effectiveness of CONSORT in improving reporting quality in journals” was published. Objectives: To update the earlier systematic review assessing whether journal endorsement of the 1996 and 2001 CONSORT checklists influences the completeness of reporting of RCTs published in medical journals. Search methods: We conducted electronic searches, known item searching, and reference list scans to identify reports of evaluations assessing the completeness of reporting of RCTs. The electronic search strategy was developed inMEDLINE and tailored to EMBASE.We searched the Cochrane Methodology Register and the Cochrane Database of Systematic Reviews using the Wiley interface. We searched the Science Citation Index, Social Science Citation Index, and Arts and Humanities Citation Index through the ISI Web of Knowledge interface. We conducted all searches to identify reports published between January 2005 and March 2010, inclusive. Selection criteria: In addition to studies identified in the original systematic review on this topic, comparative studies evaluating the completeness of reporting of RCTs in any of the following comparison groups were eligible for inclusion in this review: 1) Completeness of reporting of RCTs published in journals that have and have not endorsed the CONSORT Statement; 2) Completeness of reporting of RCTs published in CONSORT-endorsing journals before and after endorsement; or 3) Completeness of reporting of RCTs before and after the publication of the CONSORT Statement (1996 or 2001). We used a broad definition of CONSORT endorsement that includes any of the following: (a) requirement or recommendation in journal’s ’Instructions to Authors’ to follow CONSORT guidelines; (b) journal editorial statement endorsing the CONSORT Statement; or (c) editorial requirement for authors to submit a CONSORT checklist and/or flow diagram with their manuscript. We contacted authors of evaluations reporting data that could be included in any comparison group(s), but not presented as such in the published report and asked them to provide additional data in order to determine eligibility of their evaluation. Evaluations were not excluded due to language of publication or validity assessment. Data collection and analysis: We completed screening and data extraction using standardised electronic forms, where conflicts, reasons for exclusion, and level of agreement were all automatically and centrally managed in web-based management software, DistillerSR®. One of two authors extracted general characteristics of included evaluations and all data were verified by a second author. Data describing completeness of reporting were extracted by one author using a pre-specified form; a 10%random sample of evaluations was verified by a second author. Any discrepancies were discussed by both authors; we made no modifications to the extracted data. Validity assessments of included evaluations were conducted by one author and independently verified by one of three authors. We resolved all conflicts by consensus. For each comparison we collected data on 27 outcomes: 22 items of the CONSORT 2001 checklist, plus four items relating to the reporting of blinding, and one item of aggregate CONSORT scores. Where reported, we extracted and qualitatively synthesised data on the methodological quality of RCTs, by scale or score. Main results: Fifty-three publications reporting 50 evaluations were included. The total number of RCTs assessed within evaluations was 16,604 (median per evaluation 123 (interquartile range (IQR) 77 to 226) published in a median of six (IQR 3 to 26) journals. Characteristics of the included RCT populations were variable, resulting in heterogeneity between included evaluations. Validity assessments of included studies resulted in largely unclear judgements. The included evaluations are not RCTs and less than 8% (4/53) of the evaluations reported adjusting for potential confounding factors. Twenty-five of 27 outcomes assessing completeness of reporting in RCTs appeared to favour CONSORT-endorsing journals over non-endorsers, of which five were statistically significant. ’Allocation concealment’ resulted in the largest effect, with risk ratio (RR) 1.81 (99% confidence interval (CI) 1.25 to 2.61), suggesting that 81% more RCTs published in CONSORT-endorsing journals adequately describe allocation concealment compared to those published in non-endorsing journals. Allocation concealment was reported adequately in 45% (393/876) of RCTs in CONSORT-endorsing journals and in 22% (329/1520) of RCTs in non-endorsing journals. Other outcomes with results that were significant include: scientific rationale and background in the ’Introduction’ (RR 1.07, 99% CI 1.01 to 1.14); ’sample size’ (RR 1.61, 99% CI 1.13 to 2.29); method used for ’sequence generation’ (RR 1.59, 99% CI 1.38 to 1.84); and an aggregate score over reported CONSORT items, ’total sum score’ (standardised mean difference (SMD) 0.68 (99% CI 0.38 to 0.98)). Authors’ conclusions: Evidence has accumulated to suggest that the reporting of RCTs remains sub-optimal. This review updates a previous systematic review of eight evaluations. The findings of this review are similar to those from the original review and demonstrate that, despite the general inadequacies of reporting of RCTs, journal endorsement of the CONSORT Statement may beneficially influence the completeness of reporting of trials published in medical journals. Future prospective studies are needed to explore the influenc

From CFTR biology toward combinatorial pharmacotherapy:expanded classification of cystic fibrosis mutations

More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients