Systemic inflammatory markers and psychophysical olfactory scores in coronavirus disease 2019 patients: is there any correlation?

OBJECTIVE: To analyse the correlations between olfactory psychophysical scores and the serum levels of D-dimer, C-reactive protein, ferritin, lactate dehydrogenase, procalcitonin and neutrophil-to-lymphocyte ratio in coronavirus disease 2019 patients. METHODS: Patients underwent psychophysical olfactory assessment with the Connecticut Chemosensory Clinical Research Center test, and determination of blood serum levels of the inflammatory markers D-dimer, C-reactive protein, ferritin, lactate dehydrogenase, procalcitonin and neutrophil-to-lymphocyte ratio within 10 days of the clinical onset of coronavirus disease 2019 and 60 days after. RESULTS: Seventy-seven patients were included in this study. D-dimer, procalcitonin, ferritin and neutrophil-to-lymphocyte ratio correlated significantly with severe coronavirus disease 2019. No significant correlations were found between baseline and 60-day Connecticut Chemosensory Clinical Research Center test scores and the inflammatory markers assessed. CONCLUSION: Olfactory disturbances appear to have little prognostic value in predicting the severity of coronavirus disease 2019 compared to D-dimer, ferritin, procalcitonin and neutrophil-to-lymphocyte ratio. The lack of correlation between the severity and duration of olfactory disturbances and serum levels of inflammatory markers seems to further suggest that the pathogenetic mechanisms underlying the loss of smell in coronavirus disease 2019 patients are related to local rather than systemic inflammatory factors.

Role of diffusion- and perfusion-weighted MR imaging for brain tumour characterisation.

PURPOSE: This study was undertaken to correlate apparent diffusion coefficient (ADC) and relative regional cerebral blood volume (rrCBV) to histological findings in a large series of patients with primary or secondary brain tumours to evaluate diffusion-weighted (DWI) and perfusion-weighted (PWI) imaging in the characterisation of cerebral tumors. MATERIALS AND METHODS: Ninety-eight patients with cerebral tumours, 46 of which were primary (seven grade 0-I, nine low-grade gliomas, two gliomatosis cerebri, nine lymphomas and 19 high-grade gliomas) and 52 secondary, underwent conventional magnetic resonance (MR) imaging completed with DWI and dynamic contrast susceptibility PWI. Both ADC and rrCBV were calculated on a workstation by using Functool 2 software. Student's t test was used to determine any statistically significant differences in the ADC and rrCBV values. RESULTS: Seventeen of 98 tumours were cystic or necrotic (12/17 hypointense and 5/17 hyperintense on DWI); the ADC value of hyperintense cystic areas was 0.97+/-0.23x10(-3) mm2/s. The ADC value of solid tumours varied between 0.64 and 3.5x10(-3) mm2/s. The rrCBV value was 1.4 (sigma 0.66) in low-grade gliomas; 1.22 (sigma 0.25) in lymphomas; 4.5 (sigma 0.85) in grade III gliomas; 3.18 (sigma 1.26) in grade IV gliomas and 2.53 (sigma 1.6) in metastases. CONCLUSIONS: DWI has an important role in the differential diagnosis of cystic cerebral masses but not in tumour characterisation. PWI is helpful in differentiating high-from low-grade gliomas and lymphomas from high-grade gliomas.

Role of NO in endothelium-dependent relaxation of rabbit basilar artery in situ.

The purpose of this study was to investigate the possible involvement of endothelium-derived hyperpolarizing factor in endothelium-dependent relaxation of the cerebral vasculature by testing the effectiveness of NO synthase inhibitors at inhibiting endothelium-dependent relaxation in the rabbit basilar artery. Acetylcholine (1.0 microM) and 0.1/0.2 microM sarafotoxin S6c, an endothelinB receptor agonist, relaxed serotonin constricted basilar artery in situ by 100% and 70%, respectively. NG-monomethyl-L-arginine (L-NMMA; 0.1 mM) and 0.3 mM NG-nitro-L-arginine (L-NNA), NO synthase inhibitors, decreased the 1.0 microM acetylcholine- and 0.1/0.2 microM sarafotoxin S6c-induced relaxations by 75% and 45%, respectively. Unexpectedly, the relaxations were abolished by the combination of L-NMMA plus L-NNA. Furthermore, L-arginine (1.0 mM), but not D-arginine, restored the relaxations. Sodium nitroprusside-induced relaxation was also inhibited by L-NMMA plus L-NNA, and the inhibition was reversed by L-arginine. KCl constricted vessels only minimally relaxed in response to sodium nitroprusside, acetylcholine, and sarafotoxin S6c. These results demonstrate that combined NO synthase inhibitors more effectively inhibit endothelium-dependent relaxation than a single inhibitor. The mechanism underlying the greater inhibition due to the combined NO synthase inhibitors may result from both decreased NO release and secondary effects caused by decreased NO release, such as membrane depolarization. The results further suggest that caution should be used with respect to suggestions of the involvement of endothelium-derived hyperpolarizing factor in endothelium-dependent relaxation based upon the partial inhibitory effects of NO synthase inhibitors.

Does blockade of endothelinB1-receptor activation increase endothelinB2/endothelinA receptor-mediated constriction in the rabbit basilar artery?

The purpose of this study was to investigate whether endothelin (ET)-1 activation of ETB1 receptors influences the relative magnitude of ETA/ETB2 receptor-mediated ET-1 constriction in the rabbit basilar artery. Initial challenge of ET-1-constricted vessels with BQ610, an ETA-receptor antagonist, resulted in approximately 60% relaxation, and subsequent addition of BQ788, an ETB1/2-receptor antagonist, relaxed the remaining constriction. To test whether blockade of ETB1 receptors influenced the relative magnitude of ETA/ETB2 receptor-mediated constriction, ET-1-constricted vessels were exposed to RES-701-1, an ETB1-receptor antagonist, before challenge with BQ610 or BQ788. RES-701-1 enhanced the ET-1 constriction by approximately 60%, consistent with blockade of ETB1 receptor-mediated endothelium-dependent relaxation. In ET-1-constricted vessels treated with RES-701-1, BQ610 challenge resulted in complete relaxation, whereas BQ788 was without effect. However, when 10 nM acetylcholine was added to RES-701-1-treated ET-1-constricted vessels, (a) BQ610 challenge resulted in only approximately 30% relaxation, and subsequent BQ788 addition relaxed the remaining constriction; and (b) BQ788 challenge resulted in approximately 35% relaxation, and subsequent BQ610 addition relaxed the remaining constriction. Acetylcholine induced approximately 10% relaxation of RES-701-1-treated ET-1-constricted vessels. It is speculated that a dynamic relation exists between ETA and ETB2 receptor-mediated constriction, such that ET-1-induced ETB2 receptor-mediated constriction of the basilar artery is dependent on ETB1 receptor activation and, in the absence of this activation, the constriction reverts to completely ETA receptor mediated.

Endothelin ET(B1) receptor-mediated relaxation of rabbit basilar artery.

This study tests whether endothelin receptor agonist-induced relaxation of the cerebral vasculature is mediated via endothelin ET(B1) receptor activation. Sarafotoxin S6c, an endothelin ET(B) receptor agonist, relaxed rabbit basilar artery constricted with serotonin in situ. BQ788 (N-cis-2,6-dimethylpiperidinocarbonyl L-gamma-MeLeu-D-Trp (COOCH3)-Nle), and RES-701-1 (Gly-Asn-Trp-His-Gly-Thr-Ala-Pro-Asp-Trp-Phe-Phe-Asn-Tyr-Tyr-Trp), endothelin ET(B1/B2) and endothelin ET(B1) receptor antagonists, respectively, prevented sarafotoxin S6c-induced relaxation. RES-701-1 was selective for the ET(B1) receptor, as the endothelin-1 constriction elicited in the presence of BQ610 (homopiperidenyl-CO-Leu-D-Trp (CHO)-D-Trp-OH), an endothelin ET(A) receptor antagonist, was enhanced by RES-701-1, and relaxed by BQ788. These results represent the first demonstration of the presence of endothelin ET(B1) receptors in the cerebral vasculature.

Endothelin B receptor antagonists attenuate subarachnoid hemorrhage-induced cerebral vasospasm.

BACKGROUND AND PURPOSE: While it has been widely reported that the vasospasm following subarachnoid hemorrhage (SAH) is prevented/reversed by endothelin (ET) receptor antagonists selective for the ET(A) receptor and by nonselective ET receptor antagonists, ie, antagonists of both the ET(A) and ET(B) receptors, there are no reports on the possible attenuation of the spasm by selective ET(B) receptor antagonists. The purpose of this study was to investigate whether (1) ET(B) receptor antagonists prevent and reverse SAH-induced spasm and (2) attenuation of the spasm results from blockade of smooth muscle ET(B) (ET(B2)) receptor-mediated constriction and/or endothelial ET(B) (ET(B1)) receptor-mediated ET-1-induced ET-1 release. METHODS: SAH-induced spasm of the rabbit basilar artery was induced with the use of a double hemorrhage model. In vivo effects of agents on the spasm were determined by angiography after their intracisternal infusion (10 microL/h) by mini osmotic pump. In situ effects of agents on the spasm were determined by direct measurement of vessel diameter after their suffusion in a cranial window. RESULTS: SAH constricted the basilar artery by 30%. Intracisternal infusion with 10 micromol/L BQ788, an ET(B1/B2) receptor antagonist, reduced the spasm to 10%. To investigate whether BQ788 prevented the spasm by blockade of ET(B1) receptor-mediated ET-1-induced ET-1 release, as opposed to ET(B2) receptor-mediated constriction, we tested whether ET(B1) receptor blockade also prevented the spasm. Indeed, intracisternal infusion with 10 micromol/L RES-701-1, a selective ET(B1) receptor antagonist, reduced the spasm to 10%. Similarly, in situ superfusion with 1 micromol/L BQ788 reversed the spasm by 40%, and 1 micromol/L RES-701-1 reversed the spasm by 50%. However, both BQ788 and RES-701-1 enhanced by 40% to 50% the 3 nmol/L ET-1-induced constriction elicited in spastic vessels previously relaxed with 0.1 mmol/L phosphoramidon, an ET-converting enzyme inhibitor. CONCLUSIONS: These results demonstrate that ET(B) receptor antagonists prevent and reverse SAH-induced cerebral vasospasm in an animal model. The likely mechanism underlying the attenuation of the spasm is blockade of ET(B1) receptor-mediated ET-1-induced ET-1 release of newly synthesized ET-1. These studies provide rationale for the therapeutic use of ET(B1) receptor antagonists to relieve the vasospasm following SAH, as well as other pathophysiological conditions involving possible ET-1-induced ET-1 release.

Endothelin ET(B) receptor-mediated constriction in the rabbit basilar artery.

The present study tests whether endothelin ET(B) receptor activation can mediate endothelin-1 constriction in the rabbit basilar artery in situ. Endothelin-1 (30 nM) induced 27% constriction of vessels pretreated with 1 microM BQ610 (homopiperidenyl-CO-Leu-DTrp (CHO)-D-Trp-OH), an endothelin ET(A) receptor antagonist, and the resulting constriction was completely relaxed by BQ788 (N-cis-2,6-dimethylpiperidinocarbonyl L-gamma-MeLeu-D-Trp (COOCH3)-Nle), an endothelin ET(B) receptor antagonist. Similarly, 30 nM endothelin-1 induced 30% constriction of vessels pretreated with 1 microM BQ788, and the resulting constriction was completely relaxed by BQ610. In contrast, sarafotoxin S6c, an endothelin ET(B) receptor agonist, did not induce constriction. This study suggests that in the basilar artery (1) endothelin ET(B) receptor activation can result in constriction and (2) the ability to elicit constriction is in some way dependent upon the agonist that activates the endothelin ET(B) receptor.

Role of extracellular Ca2+ in subarachnoid hemorrhage-induced spasm of the rabbit basilar artery.

BACKGROUND AND PURPOSE: The role of extracellular Ca2+ in the maintenance of chronic vasospasm after subarachnoid hemorrhage (SAH) is largely unknown. Indeed, studies thus far have been limited to demonstrations that L-type Ca(2+)-channel antagonists were unable to reverse the spasm. This study tested whether SAH-induced vasospasm is maintained, at least in part. through the influx of extracellular Ca2+ and whether the influx of extracellular Ca2+ occurs through L-type Ca2+ channels and possibly, in addition, through store operated channels (SOCs). Furthermore, as there is considerable evidence in the literature to suggest that the spasm is mediated through endothelin-1 (ET-1) release, we tested whether the Ca2+ dependency of the spasm was consistent with the mediation of the spasm by ET-1. METHODS: Chronic spasm of the basilar artery was induced in a double SAH rabbit model. Relaxation of SAH-, ET-1-, serotonin-, and KC1-constricted basilar artery in response to Ca(2+)-free solution, verapamil, and Ni2+ was measured in situ with the use of a cranial window. RESULTS: SAH induced 23% constriction of the basilar artery. Ca(2+)-free solution and 1 mumol/L verapamil reversed the constriction of SAH vessels by 60% and 17%, respectively. In contrast, control vessels challenged with 40 to 50 mmol/L KCl, which induced 34% constriction, relaxed in response to Ca(2+)-free solution and verapamil by 98% and 89%, respectively. In SAH vessels, verapamil followed by 0.1 mmol/L Ni2+, which is known to block SOCs, induced a combined relaxation of 67%. Control vessels challenged with 3 nmol/L ET-1, which induced a magnitude of constriction similar to that of SAH (29%), relaxed in response to Ca(2+)-free solution, verapamil, and verapamil plus Ni2+ by 69%, 20%, and 50%, respectively (P > .05) versus respective values in SAH vessels). In contrast, control vessels challenged with 2 to 8 mumol/L serotonin, which induced a magnitude of constriction similar to those of SAH and ET-1 (22%), completely relaxed in response to Ca(2+)-free solution and verapamil. CONCLUSIONS: These results demonstrate that the maintenance of chronic spasm in the two-hemorrhage rabbit model after SAH is due to smooth muscle cell contractile mechanisms partly dependent on the influx of extracellular Ca2+. The influx of extracellular Ca2+ results from the opening of L-type Ca2+ channels and an additional channel or channels. We speculate that the L-type Ca2+ channel-independent influx of extracellular Ca2+ results from the opening of SOCs. The Ca(2+)-dependent characteristics of the spasm likely reflect the mediation of the spasm by ET-1.