Abstract
Background
Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to ...assess myocardial injury in recovered COVID-19 patients.
Methods and results
One hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection all requiring hospital admission, 48 (32%) requiring ventilatory support and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms).
Conclusions
During convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.
Graphical Abstract
The design and engineering of organic fluorescent Ca2+ indicators approximately 30 years ago opened the door for imaging cellular Ca2+ signals with a high degree of temporal and spatial resolution. ...Over this time, Ca2+ imaging has revolutionized our approaches for tissue‐level spatiotemporal analysis of functional organization and has matured into a powerful tool for in situ imaging of cellular activity in the living animal. In vivo Ca2+ imaging with temporal resolution at the millisecond range and spatial resolution at micrometer range has been achieved through novel designs of Ca2+ sensors, development of modern microscopes and powerful imaging techniques such as two‐photon microscopy. Imaging Ca2+ signals in ensembles of cells within tissue in 3D allows for analysis of integrated cellular function, which, in the case of the brain, enables recording activity patterns in local circuits. The recent development of miniaturized compact, fibre‐optic‐based, mechanically flexible microendoscopes capable of two‐photon microscopy opens the door for imaging activity in awake, behaving animals. This development is poised to open a new chapter in physiological experiments and for pharmacological approaches in the development of novel therapies.
LINKED ARTICLES This article is part of a themed section on Imaging. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2011.163.issue‐8BJP has previously published an Imaging in Pharmacology themed section, edited by A Davenport and C Daly. To view this section visit http://dx.doi.org/10.1111/bph.2010.159.issue‐4
To provide recommendations for the use of anti-tumor necrosis factor α (TNF-α) biologic agents in patients with ocular inflammatory disorders.
Ocular inflammatory diseases remain a leading cause of ...vision loss worldwide. Anti-TNF-α agents are used widely in treatment of rheumatologic diseases. A committee of the American Uveitis Society performed a systematic review of literature to generate guidelines for use of these agents in ocular inflammatory conditions.
A systematic review of published studies was performed. Recommendations were generated using the Grading of Recommendations Assessment, Development, and Evaluation group criteria.
Numerous studies including controlled clinical trials have demonstrated that anti-TNF-α biologic agents (in particular infliximab and adalimumab) are effective in the treatment of severe ocular inflammatory disease. Based on these studies, the expert panel makes the following recommendations.
Infliximab and adalimumab can be considered as first-line immunomodulatory agents for the treatment of ocular manifestations of Behçet's disease. Infliximab and adalimumab can be considered as second-line immunomodulatory agents for the treatment of uveitis associated with juvenile arthritis. Infliximab and adalimumab can be considered as potential second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions including posterior uveitis, panuveitis, severe uveitis associated with seronegative spondyloarthropathy, and scleritis in patients requiring immunomodulation in patients who have failed or who are not candidates for antimetabolite or calcineurin inhibitor immunomodulation. Infliximab and adalimumab can be considered in these patients in preference to etanercept, which seems to be associated with lower rates of treatment success.
Mutualisms that become evolutionarily stable give rise to organismal interdependencies. Some insects have developed intracellular associations with communities of bacteria, where the ...interdependencies are manifest in patterns of complementary gene loss and retention among members of the symbiosis. Here, using comparative genomics and microscopy, we show that a three-member symbiotic community has become a four-way assemblage through a novel bacterial lineage-splitting event. In some but not all cicada species of the genus Tettigades, the endosymbiont Candidatus Hodgkinia cicadicola has split into two new cytologically distinct but metabolically interdependent species. Although these new bacterial genomes are partitioned into discrete cell types, the intergenome patterns of gene loss and retention are almost perfectly complementary. These results defy easy classification: they show genomic patterns consistent with those observed after both speciation and whole-genome duplication. We suggest that our results highlight the potential power of nonadaptive forces in shaping organismal complexity.
The HLA-B27 gene is a major risk factor for clinical diseases including ankylosing spondylitis, acute anterior uveitis, reactive arthritis, and psoriatic arthritis, but its mechanism of risk ...enhancement is not completely understood. The gut microbiome has recently been shown to influence several HLA-linked diseases. However, the role of HLA-B27 in shaping the gut microbiome has not been previously investigated. In this study, we characterize the differences in the gut microbiota mediated by the presence of the HLA-B27 gene. We identified differences in the cecal microbiota of Lewis rats transgenic for HLA-B27 and human β2-microglobulin (hβ2m), compared with wild-type Lewis rats, using biome representational in situ karyotyping (BRISK) and 16S rRNA gene sequencing. 16S sequencing revealed significant differences between transgenic animals and wild type animals by principal coordinates analysis. Further analysis of the data set revealed an increase in Prevotella spp. and a decrease in Rikenellaceae relative abundance in the transgenic animals compared to the wild type animals. By BRISK analysis, species-specific differences included an increase in Bacteroides vulgatus abundance in HLA-B27/hβ2m and hβ2m compared to wild type rats. The finding that HLA-B27 is associated with altered cecal microbiota has not been shown before and can potentially provide a better understanding of the clinical diseases associated with this gene.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract The ability of bisphosphonates ((HO)2 P(O)CR1 R2 P(O)(OH)2 ) to inhibit bone resorption has been known since the 1960s, but it is only recently that a detailed molecular understanding of the ...relationship between chemical structures and biological activity has begun to emerge. The early development of chemistry in this area was largely empirical and based on modifying R2 groups in a variety of ways. Apart from the general ability of bisphosphonates to chelate Ca2+ and thus target the calcium phosphate mineral component of bone, attempts to refine clear structure–activity relationships had led to ambiguous or seemingly contradictory results. However, there was increasing evidence for cellular effects, and eventually the earliest bisphosphonate drugs, such as clodronate (R1 = R2 = Cl) and etidronate (R1 = OH, R2 = CH3 ), were shown to exert intracellular actions via the formation in vivo of drug derivatives of ATP. The observation that pamidronate, a bisphosphonate with R1 = OH and R2 = CH2 CH2 NH2 , exhibited higher potency than previously known bisphosphonate drugs represented the first step towards the later recognition of the critical importance of having nitrogen in the R2 side chain. The synthesis and biological evaluation of a large number of nitrogen-containing bisphosphonates took place particularly in the 1980s, but still with an incomplete understanding of their structure–activity relationships. A major advance was the discovery that the anti-resorptive effects of the nitrogen-containing bisphosphonates (including alendronate, risedronate, ibandronate, and zoledronate) on osteoclasts appear to result from their potency as inhibitors of the enzyme farnesyl pyrophosphate synthase (FPPS), a key branch-point enzyme in the mevalonate pathway. FPPS generates isoprenoid lipids utilized in sterol synthesis and for the post-translational modification of small GTP-binding proteins essential for osteoclast function. Effects on other cellular targets, such as osteocytes, may also be important. Over the years many hundreds of bisphosphonates have been synthesized and studied. Interest in expanding the structural scope of the bisphosphonate class has also motivated new approaches to the chemical synthesis of these compounds. Recent chemical innovations include the synthesis of fluorescently labeled bisphosphonates, which has enabled studies of the biodistribution of these drugs. As a class, bisphosphonates share common properties. However, as with other classes of drugs, there are chemical, biochemical, and pharmacological differences among the individual compounds. Differences in mineral binding affinities among bisphosphonates influence their differential distribution within bone, their biological potency, and their duration of action. The overall pharmacological effects of bisphosphonates on bone, therefore, appear to depend upon these two key properties of affinity for bone mineral and inhibitory effects on osteoclasts. The relative contributions of these properties differ among individual bisphosphonates and help determine their clinical behavior and effectiveness. This article is part of a Special Issue entitled Bisphosphonates.
Swept-source optical coherence tomography angiography (SS-OCTA) was used to measure the age-dependent changes in macular choriocapillaris (CC) flow deficits (FDs) in normal eyes.
A prospective, ...cross-sectional study.
Subjects with normal eyes ranging in age from their 20s to their 80s were imaged using a 100-kHz SS-OCTA instrument (PLEX Elite 9000, Carl Zeiss Meditec, Dublin, California, USA). Both 3 × 3-mm and 6 × 6-mm scans were used to image the macular CC. Visualization of the CC and quantification of FDs were performed using a previously validated algorithm. The percentage of FDs (FD%) in the central 1-mm circle (C1), 1.5-mm rim (R1.5), and 2.5-mm circle (C2.5) from the 3 × 3-mm and 6 × 6-mm scans and FD% in the 2.5-mm rim (R2.5) and 5-mm circle (C5) from the 6 × 6-mm scans were measured and correlated with age and axial length.
A total of 164 subjects were enrolled, with at least 10 subjects from each decade of life. No meaningful correlations were found between FD% and axial length (|r| < 0.30). FD% in all fields increased with increasing age (all r > 0.50; all P < .001); however, the greatest increases were found in the central macula C1 regions and the smallest increases in the peripheral macula R2.5 regions.
In normal aging, the FD% increased with age across the central 5 mm of the macula, but the greatest increase was found in the central 1-mm region of the macula.
Comparative genomics from mitochondria, plastids, and mutualistic endosymbiotic bacteria has shown that the stable establishment of a bacterium in a host cell results in genome reduction. Although ...many highly reduced genomes from endosymbiotic bacteria are stable in gene content and genome structure, organelle genomes are sometimes characterized by dramatic structural diversity. Previous results from Candidatus Hodgkinia cicadicola, an endosymbiont of cicadas, revealed that some lineages of this bacterium had split into two new cytologically distinct yet genetically interdependent species. It was hypothesized that the long life cycle of cicadas in part enabled this unusual lineage-splitting event. Here we test this hypothesis by investigating the structure of the Ca. Hodgkinia genome in one of the longest-lived cicadas, Magicicada tredecim . We show that the Ca. Hodgkinia genome from M. tredecim has fragmented into multiple new chromosomes or genomes, with at least some remaining partitioned into discrete cells. We also show that this lineage-splitting process has resulted in a complex of Ca. Hodgkinia genomes that are 1.1-Mb pairs in length when considered together, an almost 10-fold increase in size from the hypothetical single-genome ancestor. These results parallel some examples of genome fragmentation and expansion in organelles, although the mechanisms that give rise to these extreme genome instabilities are likely different.
Background:
Timely removal from activity after concussion symptoms remains problematic despite heightened awareness. Previous studies indicated potential adverse effects of continuing to participate ...in physical activity immediately after sustaining a concussion.
Hypothesis/Purpose:
The purpose was to determine the effect of timing of removal from play after concussion on clinical outcomes. It was hypothesized that immediate removal from activity after sport-related concussion (SRC) would be associated with less time missed from sport, a shorter symptomatic period, and better outcomes on acute clinical measures.
Study Design:
Cohort study; Level of evidence, 3.
Methods:
Data were reported from the National Collegiate Athletic Association and Department of Defense Grand Alliance: Concussion Awareness, Research, and Education (CARE) Consortium. Participants with 506 diagnosed SRCs from 18 sports and 25 institutions and military service academies were analyzed and classified as either immediate removal from activity (I-RFA) or delayed removal from activity (D-RFA). Outcomes of interest included time missed from sport attributed to their SRC, symptom duration, and clinical assessment scores.
Results:
There were 322 participants (63.6%) characterized as D-RFA. I-RFA status was associated with significantly less time missed from sport (R2 change = .022-.024, P < .001 to P = .001) and shorter symptom duration (R2 change = .044-.046, P < .001 all imputations) while controlling for other SRC recovery modifiers. These athletes missed approximately 3 fewer days from sport participation. I-RFA athletes had significantly less severe acute SRC symptoms and were at lower risk of recovery taking ≥14 days (relative risk = .614, P < .001, small-medium effect size) and ≥21 days (relative risk = .534, P = .010, small effect size).
Conclusion:
I-RFA is a protective factor associated with less severe acute symptoms and shorter recovery after SRC. Conveying this message to athletes, coaches, and others involved in the care of athletes may promote timely injury reporting.
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