The 1983shootdown of KAL 007 and the 1986 Chernobyl nuclear accident dramatically changedthe Soviet Union in unpredictable ways. The Communist Party, which struggled tomaintain control of political ...messaging after the KAL crisis, lost control inthe aftermath of Chernobyl.
In a randomized, multicenter trial involving boys with severe hemophilia A, the incidence of neutralizing antibodies to factor VIII was 87% higher with recombinant factor VIII products than with ...plasma-derived factor VIII products.
Hemophilia A is an inherited bleeding disorder characterized by plasma deficiency of coagulation factor VIII.
1
,
2
A major complication in 30% of patients is the occurrence of alloantibodies (inhibitors) that inactivate factor VIII activity and may nullify replacement therapy.
3
–
6
Risk factors include unmodifiable patient-related factors such as residual plasma factor VIII concentration and gene mutation.
7
–
9
Putative treatment-related risk factors are early replacement therapy and the source of factor VIII (i.e., human plasma or recombinant DNA technology).
3
,
8
,
10
–
13
Experimental studies have shown that plasma-derived factor VIII in complex with the chaperone protein von Willebrand factor, which masks . . .
•In vivo comet assay compared with transgenic rodent assay for 91 chemicals.•Comparison focussed on evaluation of in vivo genotoxicity per se.•Fair to good agreement between assays in GI tract ...(stomach and colon) and liver.•Poor to no agreement between assays in bone marrow.
A database of 91 chemicals with published data from both transgenic rodent mutation (TGR) and rodent comet assays has been compiled. The objective was to compare the sensitivity of the two assays for detecting genotoxicity. Critical aspects of study design and results were tabulated for each dataset. There were fewer datasets from rats than mice, particularly for the TGR assay, and therefore, results from both species were combined for further analysis. TGR and comet responses were compared in liver and bone marrow (the most commonly studied tissues), and in stomach and colon evaluated either separately or in combination with other GI tract segments. Overall positive, negative, or equivocal test results were assessed for each chemical across the tissues examined in the TGR and comet assays using two approaches: 1) overall calls based on weight of evidence (WoE) and expert judgement, and 2) curation of the data based on a priori acceptability criteria prior to deriving final tissue specific calls. Since the database contains a high prevalence of positive results, overall agreement between the assays was determined using statistics adjusted for prevalence (using AC1 and PABAK). These coefficients showed fair or moderate to good agreement for liver and the GI tract (predominantly stomach and colon data) using WoE, reduced agreement for stomach and colon evaluated separately using data curation, and poor or no agreement for bone marrow using both the WoE and data curation approaches. Confidence in these results is higher for liver than for the other tissues, for which there were less data. Our analysis finds that comet and TGR generally identify the same compounds (mainly potent mutagens) as genotoxic in liver, stomach and colon, but not in bone marrow. However, the current database content precluded drawing assay concordance conclusions for weak mutagens and non-DNA reactive chemicals.
The essays in this book examine the arguments and rhetoric used by the United States and the USSR following two catastrophes that impacted both countries, as blame is cast and consequences are ...debated. In this environment, it was perhaps inevitable that conspiracy theories would arise, especially about the downing of Korean Air Lines Flight 007 over the Sea of Japan. Those theories are examined, resulting in at least one method for addressing conspiracy arguments. In the case of Chernobyl, the disaster ruptured the "social compact" between the Soviet government and the people; efforts to overcome the resulting disillusionment quickly became the focus of state efforts.
Russia in the 1990s had a "Wild West" vibe, as reformist and conservative elements struggled for ascendancy. It was a time of heightened media freedom, a burgeoning civil society, and a quest for a ...new national identity. This volume examines the arc of official political rhetoric during this critical period.
Robert Newman epitomized the concept of the teacher-scholar. His graduate-level teaching and his scholarly pursuits were, essentially, one. The courses, while sounding general ("Evidence," "Ethical ...Presuppositions of Argument"), focused on his research interests and used those explorations to discern the credibility of evidence and the perspicacity of arguments. When it came to writing papers, pursuing research topics, even writing dissertations, Newman's students were free to pursue their own scholarly interests, using the principles uncovered in his courses and hopefully expanding, refining, and/or uncovering new measures of credibility.
Assessment of genotoxicity is a critical component of mode of action (MOA) analysis and carcinogen risk assessment due to its influence on quantitative risk extrapolation approaches. To date, clear ...guidance and expert consensus on the determination of a mutagenic MOA remains elusive, resulting in different estimates of carcinogenic risk for the same chemical among different stakeholders. Oral toxicity criteria for hexavalent chromium Cr(VI), for example, differ by orders of magnitude due largely to the interpretation of in vivo genotoxicity data. Herein, we review in vivo genotoxicity studies for Cr(VI) to inform the MOA for Cr(VI)-induced tumors observed in a two-year cancer bioassay in mice and rats exposed via drinking water. Overall, genotoxicity results in carcinogenic target tissues (viz., oral cavity and duodenum) are negative. Results in the intestine are consistent with imaging data indicating little to no chromium present in the crypt compartment following oral exposure. Positive genotoxicity results in nontarget tissues have been reported at high doses mostly following nonphysiological routes of exposure. Given the negative genotoxicity results in carcinogenic target organs from oral exposure to Cr(VI), there is scientific justification to support the use of nonlinear low-dose extrapolation methods in the derivation of oral toxicity criteria for Cr(VI). These results highlight important differences between genotoxicity testing for hazard identification purposes and quantitative risk assessment.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In a cohort of essential workers in the United States previously infected with SARS-CoV-2, risk factors for reinfection included being unvaccinated, infrequent mask use, time since first infection, ...and being non-Hispanic Black. Protecting workers from reinfection requires a multipronged approach including up-to-date vaccination, mask use as recommended, and reduction in underlying health disparities.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
• Current designs within OECD Test Guideline 488 have limitations for germ cell testing.
• The standard design for somatic tissues is not useful for mutation analysis in sperm.
• Negative mutagenic ...results in tubule germ cells with the 28 + 3d design are unreliable.
• The 28 + 28d design may be appropriate for both somatic tissues and germ cells.
The Organisation for Economic Co-operation and Development Test Guideline 488 (TG 488) provides recommendations for assessing germ cell and somatic cell mutagenicity using transgenic rodent (TGR) models. However, important data gaps exist for selecting an optimal approach for simultaneously evaluating mutagenicity in both cell types. It is uncertain whether analysis of germ cells from seminiferous tubules (hereafter, tubule germ cells) or caudal sperm within the recommended design for somatic tissues (i.e., 28 days of exposure plus three days of fixation time, 28 + 3d) has enough sensitivity to detect an effect as compared with the analysis of sperm within the recommended design for germ cells (i.e., 28 + 49d and 28 + 70d for mouse and rat, respectively). To address these data gaps, the Germ Cell workgroup of the Genetic Toxicology Technical Committee of the Health and Environmental Sciences Institute reviewed the available TGR mutagenicity data in male germ cells, and, characterized the exposure history of tubule germ cells for different sampling times to evaluate its impact on germ cell mutagenicity testing using TG 488. Our analyses suggest that evaluating mutant frequencies in: i) sperm from the cauda epididymis at 28 + 3d does not provide meaningful mutagenicity data; ii), tubule germ cells at 28 + 3d provides reliable mutagenicity data only if the results are positive; and iii) tubule germ cells at 28 + 28d produces reliable positive and negative results in both mice and rats. Thus, the 28 + 28d regimen may provide an approach for simultaneously assessing mutagenicity in somatic tissues and germ cells from the same animals. Further work is required to support the 28 + 28d protocol for tissues other than slowly proliferating tissues as per current TG 488. Finally, recommendations are provided to guide the experimental design for germ cell mutagenicity data for regulatory submission, as well as other possible approaches to increase the reliability of the TGR assay.
Objective To investigate the relationship between abdominal ultrasound findings and demographic, historical, and clinical features in children with cystic fibrosis (CF). Study design Children age ...3-12 years with CF without known cirrhosis, were enrolled in a prospective, multicenter study of ultrasound to predict hepatic fibrosis. Consensus ultrasound patterns were assigned by 3 radiologists as normal, heterogeneous, homogeneous, or cirrhosis. Data were derived from direct collection and US or Toronto CF registries. χ2 or ANOVA were used to compare variables among ultrasound groups and between normal and abnormal. Logistic regression was used to study risk factors for having abnormal ultrasound. Results Findings in 719 subjects were normal (n = 590, 82.1%), heterogeneous (64, 8.9%), homogeneous (41, 5.7%), and cirrhosis (24, 3.3%). Cirrhosis ( P = .0004), homogeneous ( P < .0001), and heterogeneous ( P = .03) were older than normal. More males were heterogeneous ( P = .001). More heterogeneous (15.0%, P = .009) and cirrhosis (25.0%, P = .005) had CF-related diabetes or impaired glucose tolerance vs normal (5.4%). Early infection with Pseudomonas aeruginosa (<2 years old) was associated with a lower risk (OR 0.42, P = .0007) of abnormal. Ursodeoxycholic acid use (OR 3.69, P < .0001) and CF-related diabetes (OR 2.21, P = .019) were associated with increased risk of abnormal. Conclusions Unsuspected cirrhosis is seen in 3.3% of young patients with CF, heterogeneous in 8.9%. Abnormal ultrasound is associated with CF-related diabetes, and early P aeruginosa is associated with normal ultrasound. Prospective assessment of these risk factors may identify potential interventional targets. Trial registration ClinicalTrials.gov : NCT01144507.
PDF
