Kinin receptors: functional aspects

Two types of receptors (B1R, B2R) for kinins are defined in mammalian species. Comparative experiments involving recombinant fusion proteins consisting of rabbit B1R or B2R fused to GFP-related proteins are exploited to study the regulation of the response to kinins at the receptor level. The following points will be briefly reviewed and supported by some novel data. (1) The constitutive B2Rs are internalized upon agonist stimulation, but completely recycled to the cell surface; however, B2R destruction can be achieved following limited proteolysis (extracellular trypsin, neutrophil proteases), a plausible down-regulation mechanism in pathology. (2) The inducible B1Rs, stimulated by des-Arg9-kinins, are not phosphorylated nor internalized upon agonist stimulation, but rather undergo a reversible redistribution to caveolae-related rafts. B2Rs are also subjected to this translocation, but only transiently (before endocytosis). (3) Based on the analysis of rabbit aortic smooth muscle cells, B1R induction by cytokines is dependent on nuclear factor KB in rabbit vascular tissue, but exogenous kinins acting on either receptor type do not induce B1R expression.     

The impact of inefficient clinical diagnosis on the cost of managing low back pain

The clinical examination remains the pivotal factor in evaluating low back pain (LBP) for decisions concerning compensation and rehabilitation. Many practitioners believe it to be highly reliable, even though existing literature does not support this belief. Not only are there no data supporting the efficacy of clinical diagnosis for LBP, but also published data underscore its many inherent weaknesses. Healthcare risk managers need accurate clinical information to make decisions. If current clinical information is unreliable, then healthcare risk management strategies for LBP must be revised.     

Spread of Multidrug-Resistant Rhodococcus equi,United States

Multidrug resistance has been detected in the animal and zoonotic human pathogen Rhodococcus equi after mass macrolide/rifampin antibioprophylaxis in endemically affected equine farms in the United States. Multidrug-resistant (MDR) R. equi emerged upon acquisition of pRERm46, a conjugative plasmid conferring resistance to macrolides, lincosamides, streptogramins, and, as we describe, tetracycline. Phylogenomic analyses indicate that the increasing prevalence of MDR R. equi since it was first documented in 2002 is caused by a clone, R. equi 2287, attributable to coselection of pRErm46 with a chromosomal rpoB^S531F mutation driven by macrolide/rifampin therapy. pRErm46 spillover to other R. equi genotypes has given rise to a novel MDR clone, G2016, associated with a distinct rpoB^S531Y mutation. Our findings illustrate that overuse of antimicrobial prophylaxis in animals can generate MDR pathogens with zoonotic potential. MDR R. equi and pRErm46-mediated resistance are currently disseminating in the United States and are likely to spread internationally through horse movements.     

From the Cover: Global declines in coral reef calcium carbonate production under ocean acidification and warming

Ocean warming and acidification threaten the future growth of coral reefs. This is because the calcifying coral reef taxa that construct the calcium carbonate frameworks and cement the reef together are highly sensitive to ocean warming and acidification. However, the global-scale effects of ocean warming and acidification on rates of coral reef net carbonate production remain poorly constrained despite a wealth of studies assessing their effects on the calcification of individual organisms. Here, we present global estimates of projected future changes in coral reef net carbonate production under ocean warming and acidification. We apply a meta-analysis of responses of coral reef taxa calcification and bioerosion rates to predicted changes in coral cover driven by climate change to estimate the net carbonate production rates of 183 reefs worldwide by 2050 and 2100. We forecast mean global reef net carbonate production under representative concentration pathways (RCP) 2.6, 4.5, and 8.5 will decline by 76, 149, and 156%, respectively, by 2100. While 63% of reefs are projected to continue to accrete by 2100 under RCP2.6, 94% will be eroding by 2050 under RCP8.5, and no reefs will continue to accrete at rates matching projected sea level rise under RCP4.5 or 8.5 by 2100. Projected reduced coral cover due to bleaching events predominately drives these declines rather than the direct physiological impacts of ocean warming and acidification on calcification or bioerosion. Presently degraded reefs were also more sensitive in our analysis. These findings highlight the low likelihood that the world’s coral reefs will maintain their functional roles without near-term stabilization of atmospheric CO₂ emissions.

Coral reef ecosystems provide a habitat for a vast array of biodiversity (1, 2), yield billions of dollars of global revenue from fisheries and tourism (3, 4), and protect tropical shorelines from hazards such as storms (5). These functions are dependent on the maintenance of the framework structure of the reefs, the accumulation of which requires the net production of calcium carbonate by resident taxa. This net calcium carbonate production is a balance between gross production minus the loss due to physical, chemical, and biological erosion. However, the net calcium carbonate production and related potential vertical accretion of reefs is increasingly threatened by anthropogenic climate change (5). Vertical reef accretion is the product of a number of processes that include 1) biological net calcium carbonate production (gross production by calcifying taxa minus bioerosion), 2) net sediment production (gross production minus endolithic and pore water–driven dissolution), 3) sediment transport (import and export), 4) physical erosion, and 5) cementation rates (Fig. 1). We refer to this potential vertical accretion of reefs simply as “accretion” hereafter, and note that we focus on sediment dissolution and biological net carbonate production (hereafter referred to as “net carbonate production,” the measurement of which is referred to as “carbonate budgets”), perhaps the best quantified and largest contributors to accretion rates on reefs on short timescales.Open in a separate windowFig. 1.Processes involved in net carbonate production and accretion on reefs as well as the associated methods typically employed to measure this. +ve = positive contribution to accretion with solid lines; −ve = negative contribution with dashed lines. Processes in gray are not included in most carbonate budgets or here. Here, we project the effects of ocean acidification and warming on CCA and coral calcification, chemical components of bioerosion, and sediment dissolution. Only chemical components of bioerosion are included in hydrochemical measurements, while direct sediment production by bioeroders is also included here.Climate change will impact both the abundance and calcification rates of reef taxa responsible for producing calcium carbonate, such as corals and coralline algae (2, 6, 7), while simultaneously altering the bioerosion and recycling of this calcium carbonate by resident bioeroders, such as sponges and cyanobacteria (8, 9). Both net carbonate production and accretion are already declining regionally in response to fishing pressure, disease, and marine heatwaves (10–13). Such changes have profound implications for societally relevant ecosystem service provisioning (11), and rapid climate change impacts are projected to further exacerbate these negative trajectories. Specifically, ocean warming and associated marine heatwaves will reduce gross carbonate production rates on coral reefs, as coral cover is reduced by more frequent and severe mass bleaching events (14–16) and as elevated temperatures decrease the calcification rates of coral and coralline algae under more severe warming scenarios (6, 17). Ocean acidification is also projected to reduce the calcification rates of key taxa such as corals and coralline algae that form reef structures and associated sediments (6, 7, 18, 19) while further reducing accretion by increasing the dissolution of carbonate sediments (20) and enhancing rates of bioerosion (8, 9). Furthermore, the combined impacts of ocean warming and acidification are predicted to be amplified under higher CO₂ emission scenarios (6, 19).While the responses of reef-forming taxa to ocean warming and acidification have been the focus of considerable scientific effort in recent decades (2, 6, 7), quantitative predictions of the impacts of climate change on global coral reef net carbonate production and reef accretion are limited. Specifically, existing projections are largely theoretical, limited to specific locations, only include sea level rise and not ocean acidification or warming, or do not include some of the major processes controlling coral reef net carbonate production (5, 10, 20–23). For example, one prominent model provided important data on lagoon sediment dissolution rates (20), although the link between changes in these rates and forereef accretion is unclear. Other global-scale projections do not include the impacts of ocean warming or acidification (5). How the combined effects of changes in the mortality, calcification, and bioerosion rates of individual reef taxa will manifest spatially across different ocean basins due to ocean warming and acidification remains unresolved.Predicting the trajectories of future net carbonate production is complicated by uncertainties around the magnitude of future declines in coral cover, which is likely to be one of the major drivers of future carbonate budgets of coral reefs; yet, estimating future coral cover is difficult. While coral cover is declining globally due to repeated mass coral bleaching (hereafter referred to as “bleaching”) and other local stressors, there is clear temporal and spatial variability of local anthropogenic impacts (16, 24–26). This makes estimating future coral cover a complex and heavily debated process, even on local scales (27–29). The impacts of marine heatwaves on coral mortality, recovery, and subsequent recruitment cannot be captured accurately in short-term laboratory experiments in the way that changes to calcification can, and currently available projections of coral cover into the future are encumbered with uncertainties that do not allow us to predict exact future cover for any specific region (16, 30, 31).Here, we resolve these challenges of applying laboratory results to real coral reef locations by assessing changes in future carbonate budgets of reefs as a function of integrated robust estimates of the responses of major components of the carbonate budget to climate change as well as including estimates of changes in future coral cover. We collate or measure data from 233 locations on 183 distinct reefs globally (49% Atlantic, 39% in the Indian, and 11% in the Pacific Ocean) to quantify the impacts of ocean warming and acidification on coral reef net carbonate production and then use these data to estimate the impacts on net carbonate production and accretion by 2050 and 2100. We incorporate more than 800 empirically measured changes in net calcification rates of the main producers of calcium carbonate on coral reefs (corals and coralline algae), bioerosion rates, and sediment dissolution in response to ocean warming, acidification, and their interaction from 98 studies. We model the size of the effects of ocean acidification, ocean warming, and their interaction under contrasting Intergovernmental Panel on Climate Change emissions scenarios for representative concentration pathways (RCP) 2.6, 4.5, and 8.5 for the year 2050 and 2100. We then apply these estimated effects to reefs with previously measured rates of net carbonate production, where the cover of corals and coralline algae is well defined (SI Appendix, Table S1). Importantly, we account for the impact of reduced coral cover, which, in most locations, will be further diminished by more severe and frequent bleaching events (16, 25), including estimates of its impacts based on currently available information. We calculate region-specific projections of degree heating weeks (DHW), a commonly used metric that accounts for the severity and duration of marine heatwaves on corals (32) and combine them with reductions in coral cover that were measured after exposure to differing DHWs during the 2016 El Niño event (25). These models (Materials and Methods) are then used to explore the effects of ocean warming and acidification independently, and in interaction with each other, under each climatic scenario on rates of reef net carbonate production and accretion.     

Diagnostic evaluation and management of chronic thromboembolic pulmonary hypertension: A clinical practice guideline

BACKGROUND

Pulmonary embolism is a common condition. Some patients subsequently develop chronic thromboembolic pulmonary hypertension (CTEPH). Many care gaps exist in the diagnosis and management of CTEPH patients including lack of awareness, incomplete diagnostic assessment, and inconsistent use of surgical and medical therapies.

METHODS

A representative interdisciplinary panel of medical experts undertook a formal clinical practice guideline development process. A total of 20 key clinical issues were defined according to the patient population, intervention, comparator, outcome (PICO) approach. The panel performed an evidence-based, systematic, literature review, assessed and graded the relevant evidence, and made 26 recommendations.

RESULTS

Asymptomatic patients postpulmonary embolism should not be screened for CTEPH. In patients with pulmonary hypertension, the possibility of CTEPH should be routinely evaluated with initial ventilation/ perfusion lung scanning, not computed tomography angiography. Pulmonary endarterectomy surgery is the treatment of choice in patients with surgically accessible CTEPH, and may also be effective in CTEPH patients with disease in more ‘distal’ pulmonary arteries. The anatomical extent of CTEPH for surgical pulmonary endarterectomy is best assessed by contrast pulmonary angiography, although positive computed tomography angiography may be acceptable. Novel medications indicated for the treatment of pulmonary hypertension may be effective for selected CTEPH patients.

CONCLUSIONS

The present guideline requires formal dissemination to relevant target user groups, the development of tools for implementation into routine clinical practice and formal evaluation of the impact of the guideline on the quality of care of CTEPH patients. Moreover, the guideline will be updated periodically to reflect new evidence or clinical approaches.     

Fibroblast growth factor homologous factor 1 (FHF1) is expressed in a subpopulation of calcitonin gene-related peptide-positive nociceptive neurons in the murine dorsal root ganglia

Dorsal root ganglia (DRG) neurons exhibit a wide molecular heterogeneity in relation to the various sensory modalities (mechanoception, thermoception, nociception) that they subserve. Finding markers of subpopulations is an important step in understanding how these neurons convey specific information. We identified fibroblast growth factor homologous factor 1 (FHF1) in a search for markers of subpopulations of DRG neurons. FHFs constitute a family of four factors that share some structural properties with fibroblast growth factors (FGFs) but are functionally distinct. They are expressed in specific subsets of neurons and are involved in the modulation of sodium channel activity. The pattern of expression of FHF1 in the DRG was determined during development, in the adult and after axotomy. We show that in the adult, FHF1 is expressed in two populations, one composed of nociceptors and another in which no neurotrophic factor receptors were detected (panTrk-/c-Ret-). Interestingly, in the nociceptors, FHF1 expression was restricted to a subset of TrkA+/calcitonin gene-related peptide (CGRP)-positive neurons. Neurofilament 200 (NF-200) and peripherin labeling indicates that 70% of the FHF1-expressing neurons contribute to A-fibers and 30% to C-fibers. FHF1 interacts with the Na(v)1.9 sodium channel isoform, which is strongly expressed in cRet+/isolectin-B4 binding neurons, but we show that FHF1 is not expressed in the cRet+/IB4+ subclass and that it does not colocalize with Na(v)1.9. Our results argue strongly against the possibility that FHF1 has a modulatory effect on this channel in cRet+/IB4+ neurons, but FHF1 could play a role in a distinct subset of TrkA+/CGRP+ nociceptors.     

Retrobulbar anesthesia during keratolplasty

AIM: A restrospective study was carried in order to evaluate the efficacy and safety of retrobulbar anaesthesia during keratoplasty. METHODS: Of 250 consecutive keratoplasty, 30 (12%) were performed under retrobulbar anaesthesia. Patients received a mean volume of 12 ml, composed of etidocaine (2/3), bupicaine (1/3) and hyaluronidase. Ocular compression duration was at least 20 minutes. RESULTS: Surgery was found painless by 90% of patients. Akinesia was complete in 80% of cases. CONCLUSION: Theses results demonstrate that retrobulbar anaesthesia may be recommended to this type of surgery.