MECHANISMS OF DISEASE Acute Oxygen-Sensing Mechanisms

JOSEPH PRIESTLEY, ONE OF THE THREE SCIENTISTS CREDITED WITH THE discovery of oxygen, described the death of mice that were deprived of oxygen. However, he was also well aware of the toxicity of too much oxygen, stating, “For as a candle burns much faster in dephlogisticated [oxygen enriched] than in common air, so we might live out too fast, and the animal powers be too soon exhausted in this pure kind of air. A moralist, at least, may say, that the air which nature has provided for us is as good as we deserve.”1 In this review we examine the remarkable mechanisms by which different organs detect and respond to acute changes in oxygen tension. Specialized tissues that sense the local oxygen tension include glomus cells of the carotid body, neuroepithelial bodies in the lungs, chromaffin cells of the fetal adrenal medulla, and smooth-muscle cells of the resistance pulmonary arteries, fetoplacental arteries, systemic arteries, and the ductus arteriosus. Together, they constitute a specialized homeostatic oxygen-sensing system. Although all tissues are sensitive to severe hypoxia, these specialized tissues respond rapidly to moderate changes in oxygen tension within the physiologic range (roughly 40 to 100 mm Hg in an adult and 20 to 40 mm Hg in a fetus)Junta de Andalucí

Human Infection from an Unidentified Erythrocyte-Associated Bacterium

Abstract A 49-year-old splenectomized man had an infection from an unidentified, gram-positive, rodshaped bacterium that adhered to the majority of his peripheral-blood erythrocytes. On transmission electron microscopy, the bacterium was seen to be extraerythrocytic and was 0.2 μm wide by 1.0 to 1.7 μm long. It possessed a thick, granular cell wall, a trilamellar membrane external to the cell wall and prominent mesosomes. Attempts to cultivate the organism in vitro or to duplicate the patient\u27s disease in splenectomized animals were unsuccessful. The patient\u27s response suggested that the bacterium was susceptible to cell-wall-active antibiotics and to chloramphenicol but not to tetracycline. This bacterium may be the cause of other chronic, fever-producing, multisystem diseases of unknown origin. (N Engl J Med 301:897–900, 1979

First known extinct feathertail possums (Acrobatidae, Marsupialia): palaeobiodiversity, phylogenetics, palaeoecology and palaeogeography

Four new fossil feathertail possum species (Marsupialia, Diprotodontia, Phalangerida, Petauroidea, Acrobatidae) are described from late Oligocene to middle Miocene fossil deposits in the Riversleigh World Heritage Area, northwestern Queensland. They are the first pre-Pleistocene fossil representatives of this family to be described. Two species are referred to the modern genus Acrobates and two to the modern genus Distoechurus. These species are distinguished from each other and from the living Distoechurus pennatus and Acrobates pygmaeus on the basis of qualitative and quantitative characters of the first lower molar (m1), which is the only tooth known for all four fossil species. Fortunately, m1 is morphologically the most variable tooth in the cheektooth row of acrobatids, and it exhibits numerous genus- and species-specific features. Phylogenetic analyses based on dental characters strongly support monophyly of Acrobatidae relative to other petauroids, as well as providing relatively strong support for reciprocal monophyly of Acrobates and Distoechurus, including the newly described fossil members of these genera. Recognition of species of Acrobates and Distoechurus in these fossil deposits is broadly congruent with recent estimates for the time of divergence of the two modern genera based on molecular data, and also provides an additional fossil calibration point for future studies of marsupial divergence times. These fossil species provide new insights into the biogeographical and ecological history of this enigmatic family of small possums, specifically that the oldest known species of Acrobates occurred in closed forest environments (in contrast to the living species, A. pygmaeus and Acrobates frontalis, which today inhabit open sclerophyll forests and woodlands) and that Distoechurus appears to have originated in Australia, only subsequently dispersing to New Guinea before becoming extinct in its Australian homeland

Rheumatoid arthritis treated with 6-months of first-line biologic or biosimilar therapy: an updated systematic review and network meta-analysis.

OBJECTIVES: The aim of this study was to estimate the effectiveness of first-line biologic disease modifying drugs(boDMARDs), and their approved biosimilars (bsDMARDs), compared with conventional (csDMARD) treatment, in terms of ACR (American College of Rheumatology) and EULAR (European League against Rheumatism) responses. METHODS: Systematic literature search, on eight databases to January 2017, sought ACR and EULAR data from randomized controlled trials (RCTs) of boDMARDs / bsDMARDs (in combination with csDMARDs, or monotherapy). Two adult populations: methotrexate (MTX)-naïve patients with severe active RA; and csDMARD-experienced patients with moderate-to-severe active RA. Network meta-analyses (NMA) were conducted using a Bayesian Markov chain Monte Carlo simulation using a random effects model with a probit link function for ordered categorical. RESULTS: Forty-six RCTs met the eligibility criteria. In the MTX-naïve severe active RA population, no biosimilar trials meeting the inclusion criteria were identified. MTX plus methylprednisolone (MP) was most likely to achieve the best ACR response. There was insufficient evidence that combination boDMARDs was superior to intensive (two or more) csDMARDs. In the csDMARD-experienced, moderate-to-severe RA population, the greatest effects for ACR responses were associated with tocilizumab (TCZ) monotherapy, and combination therapy (plus MTX) with bsDMARD etanercept (ETN) SB4, boDMARD ETN and TCZ. These treatments also had the greatest effects on EULAR responses. No clear differences were found between the boDMARDs and their bsDMARDs. CONCLUSIONS: In MTX-naïve patients, there was insufficient evidence that combination boDMARDs was superior to two or more csDMARDs. In csDMARD-experienced patients, boDMARDs and bsDMARDs were comparable and all combination boDMARDs / bsDMARDs were superior to single csDMARD

The cost-effectiveness of sequences of biological disease-modifying antirheumatic drug treatment in England for patients with rheumatoid arthritis who can tolerate methotrexate.

Objective: To ascertain whether strategies of treatment with a biological diseasemodifying antirheumatic drug (bDMARD) were cost-effective in an English setting. Results are presented for those patients with moderate-to-severe rheumatoid arthritis (RA) and those with severe RA. Methods: An economic model to assess the cost-effectiveness of seven bDMARDs was developed. A systematic literature review and network meta-analysis was undertaken to establish relative clinical effectiveness. The results together with estimates of: Health Assessment Questionnaire (HAQ) score following European League Against Rheumatism response; annual costs, and utility, per HAQ band; trajectory of HAQ for patients on bDMARDs; and trajectory of HAQ for patients on non-biologic therapy (NBT) were used to populate the model. Results were presented as those associated with the strategy with the median cost-effectiveness. Supplementary analyses were undertaken assessing the change in cost-effectiveness where only patients with the most severe prognoses on NBT were provided with bDMARD treatment. The cost per QALY values were compared with reported thresholds from the National Institute for Health and Care Excellence of £20,000 to £30,000. Results: In the primary analyses, the cost per QALY of a bDMARD strategy was £41,600 for patients with severe RA and £51,100 for those with moderate-to-severe RA. Under the supplementary analyses the cost per QALY fell to £25,300 for those with severe RA and to £28,500 for those with moderate-to-severe RA. Conclusion: The cost-effectiveness of bDMARDs in RA in England is questionable and only meets current accepted levels in subsets of patients with the worst prognoses

SARS-CoV-2 variants of interest and concern naming scheme conducive for global discourse

A group convened and led by the Virus Evolution Working Group of the World Health Organization reports on its deliberations and announces a naming scheme that will enable clear communication about SARS-CoV-2 variants of interest and concern.Molecular basis of virus replication, viral pathogenesis and antiviral strategie

More than smell - COVID-19 is associated with severe impairment of smell, taste, and chemesthesis

Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change ±100) revealed a mean reduction of smell (-79.7 ± 28.7, mean ± standard deviation), taste (-69.0 ± 32.6), and chemesthetic (-37.3 ± 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis. The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms. © 2020 The Author(s) 2020. Published by Oxford University Press. All rights reserved

Mouse Chromosome 11

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46996/1/335_2004_Article_BF00648429.pd