Of mice and human embryos:is there an ethically preferred order of preclinical research on new assisted reproductive technologies?

It is widely acknowledged that the responsible introduction of new assisted reproductive technologies (ARTs) requires preclinical safety research, including the use of animal models and human embryos. However, the moral sensitivity of human embryo research has led to regulations and guidance stating that human embryos may only be used for research that cannot also be conducted with animals. We call this the 'use animals first' (UAF) rule. In the field of ART research, this translates into the notion of an ideal chain of consecutive preclinical research steps, where research using human embryos may only be considered as a further step after promising results have been obtained in animals first. This may lead to research ethics committees requiring animal studies that are in fact a waste of time and money, while exposing animals to an infringement of their wellbeing for no good purpose. In this paper, we explore the possible moral arguments behind the UAF-rule and test their validity. We conclude that there are no convincing grounds for upholding this rule and recommend replacing it.</p

Effectiveness of Remdesivir Treatment Protocols among Patients Hospitalized with COVID-19: A Target Trial Emulation

Background: Remdesivir is recommended for certain hospitalized patients with COVID-19. However, these recommendations are based on evidence from small randomized trials, early observational studies, or expert opinion. Further investigation is needed to better inform treatment guidelines with regard to the effectiveness of remdesivir among these patients. Methods: We emulated a randomized target trial using chargemaster data from 333 US hospitals from 1 May 2020 to 31 December 2021. We compared three treatment protocols: remdesivir within 2 days of hospital admission, no remdesivir within the first 2 days of admission, and no remdesivir ever. We used baseline comorbidities recorded from encounters up to 12 months before admission and identified the use of in-hospital medications, procedures, and oxygen supplementation from charges. We estimated the cumulative incidence of mortality or mechanical ventilation/extracorporeal membrane oxygenation with an inverse probability of censoring weighted estimator. We conducted analyses in the total population as well as in subgroups stratified by level of oxygen supplementation. Results: A total of 274,319 adult patients met the eligibility criteria for the study. Thirty-day in-hospital mortality risk differences for patients adhering to the early remdesivir protocol were -3.1% (95% confidence interval = -3.5%, -2.7%) compared to no early remdesivir and -3.7% (95% confidence interval -4.2%, -3.2%) compared to never remdesivir, with the strongest effect in patients needing high-flow oxygen. For mechanical ventilation/extracorporeal membrane oxygenation, risk differences were minimal. Conclusions: We estimate that, among hospitalized patients with COVID-19, remdesivir treatment within 2 days of admission reduced 30-day in-hospital mortality, particularly for patients receiving supplemental oxygen on the day of admission

Tomato: a crop species amenable to improvement by cellular and molecular methods

Tomato is a crop plant with a relatively small DNA content per haploid genome and a well developed genetics. Plant regeneration from explants and protoplasts is feasable which led to the development of efficient transformation procedures. In view of the current data, the isolation of useful mutants at the cellular level probably will be of limited value in the genetic improvement of tomato. Protoplast fusion may lead to novel combinations of organelle and nuclear DNA (cybrids), whereas this technique also provides a means of introducing genetic information from alien species into tomato. Important developments have come from molecular approaches. Following the construction of an RFLP map, these RFLP markers can be used in tomato to tag quantitative traits bred in from related species. Both RFLP's and transposons are in the process of being used to clone desired genes for which no gene products are known. Cloned genes can be introduced and potentially improve specific properties of tomato especially those controlled by single genes. Recent results suggest that, in principle, phenotypic mutants can be created for cloned and characterized genes and will prove their value in further improving the cultivated tomato.

Soman-induced convulsions: the neuropathology revisited.

The organophosphorus compound soman, an irreversible inhibitor of cholinesterases, produces seizure activity and related brain damage. Studies using various biochemical markers of programmed cell death (PCD) suggested that soman-induced cell damage in the brain was apoptotic rather than necrotic. However, it has recently become clear that not all PCD is apoptotic, and the unequivocal demonstration of apoptosis requires ultrastructural examination. Therefore, the present study was undertaken to reinvestigate the damage produced in the brains of mice sacrificed at various times within the first 24 h or at 7 days after a convulsive dose of soman. Classical histology and ultrastructural examination were performed. The immunohistochemical expression of proteins (p53, Bax) involved in PCD, DNA fragmentation (TUNEL method at light and electron microscopy levels) and the glial reaction were also explored. Our study confirms that the severity of lesions depended on the duration of convulsions and shows that cerebral changes were still occurring as late as 7 days after the onset of long-lasting convulsions. Our observations also establish that there was a large variety of ultrastructurally distinct types of cell damage, including hybrid forms between apoptosis and necrosis, but that pure apoptosis was very rare. A prominent expression of p53 and Bax proteins was detected indicating that PCD mechanisms were certainly involved in the morphologically diverse forms of cell death. Since purely apoptotic cells were very rare, these protein expressions were presumably involved either in nonapoptotic cell death mechanisms or in apoptotic mechanisms occurring in parallel with nonapoptotic ones. Moreover, evidence for DNA fragmentation by the TUNEL method was found in apoptotic but also in numerous other morphotypes of cell damage. Therefore, TUNEL-positivity and the expression of PCD-related proteins, in the absence of ultrastructural confirmation, were here shown not to provide proof of apoptosis. In soman poisoning as well as in other cerebral pathologies, premature conclusions on this question can potentially be misleading and might even lead to detrimental therapies

Infliximab in Recalcitrant Severe Atopic Eczema Associated with Contact Allergy

n/

Identification and characterization of an anti-tyrosine kinase factor in cystic gliomas

In view of the frequent activation of the epidermal growth factor receptor (EGF-R) in gliomas and autocrine hypothesis, we searched for 'EGF-like' factor(s) in cystic fluids (CFs) associated with gliomas. Membranes of A431 cells, which overexpress EGF-R, were used to explore such activity in 20 CFs. In all cases CFs induced inhibition of EGF-R phosphorylation. Biochemical analysis revealed an anti-tyrosine kinase activity which was identified as a 18 kDa proteic factor. Effectiveness at high dilution and anti-proliferative effect on living cells in culture suggest that this factor may be involved in the negative regulation of glial oncogenesis