β<Subscript>3</Subscript> phosphorylation of platelet α<Subscript>IIb</Subscript>β<Subscript>3</Subscript> is crucial for stability of arterial thrombus and microparticle formation in vivo

Background

It is well accepted that functional activity of platelet integrin α_IIbβ₃ is crucial for hemostasis and thrombosis. The β₃ subunit of the complex undergoes tyrosine phosphorylation shown to be critical for outside-in integrin signaling and platelet clot retraction ex vivo. However, the role of this important signaling event in other aspects of prothrombotic platelet function is unknown.

Method

Here, we assess the role of β₃ tyrosine phosphorylation in platelet function regulation with a knock-in mouse strain, where two β₃ cytoplasmic tyrosines are mutated to phenylalanine (DiYF). We employed platelet transfusion technique and intravital microscopy for observing the cellular events involved in specific steps of thrombus growth to investigate in detail the role of β₃ tyrosine phosphorylation in arterial thrombosis in vivo.

Results

Upon injury, DiYF mice exhibited delayed arterial occlusion and unstable thrombus formation. The mean thrombus volume in DiYF mice formed on collagen was only 50% of that in WT. This effect was attributed to DiYF platelets but not to other blood cells and endothelium, which also carry these mutations. Transfusion of isolated DiYF but not WT platelets into irradiated WT mice resulted in reversal of the thrombotic phenotype and significantly prolonged blood vessel occlusion times. DiYF platelets exhibited reduced adhesion to collagen under in vitro shear conditions compared to WT platelets. Decreased platelet microparticle release after activation, both in vitro and in vivo, were observed in DiYF mice compared to WT mice.

Conclusion

β₃ tyrosine phosphorylation of platelet α_IIbβ₃ regulates both platelet pro-thrombotic activity and the formation of a stable platelet thrombus, as well as arterial microparticle release.

     

Imaging VEGF Receptors and α<Subscript>v</Subscript>β<Subscript>3</Subscript> Integrins in a Mouse Hindlimb Ischemia Model of Peripheral Arterial Disease

Purpose

To compare targeted imaging of vascular endothelial growth factor (VEGF) receptors vs. α_vβ₃ integrins in a mouse hindlimb ischemia model of peripheral artery disease.

Procedures

Male wild-type (WT) C57BL/6 mice (8- to 10-week old) (n?=?24) underwent left femoral artery ligation. The right leg served as control. Five days later, mice were injected with either VEGF receptor targeting [^99mTc]DOTA-PEG-scVEGF ([^99mTc]scV) (n?=?8) or with α_vβ₃-targeting tracer [^99mTc]HYNIC-cycloRGD ([^99mTc]RGD) (n?=?8) and underwent single photon emission computed tomography (SPECT) x-ray computed tomography imaging. To assess non-specific [^99mTc]scV uptake, six additional mice received a mixture of [^99mTc]scV and 30-fold excess of targeting protein, scVEGF. Tracer uptake as %ID was measured using volumetric regions encompassing the hindlimb muscles and as %ID/g from harvested limb muscles. Double and triple immunofluorescent analysis on tissue sections established localization of α_vβ₃, VEGFR-1, VEGFR-2, as well as certain cell lineage markers.

Results

Tracer uptake, as %ID/g, was higher in ligated limbs of mice injected with [^99mTc]scV compared to ligated hindlimbs in mice injected with [^99mTc]RGD (p?=?0.02). The ratio of tracer uptake for ligated/control hindlimb was borderline higher for [^99mTc]scV than for [^99mTc]RGD (p?=?0.06). Immunofluorescent analysis showed higher prevalence of VEGFR-1, VEGFR-2, and α_vβ₃, in damaged vs. undamaged hindlimb tissue, but with little co-localization of these markers. Double immunofluorescent staining showed partial co-localization of VEGFR-1, VEGFR-2, and α_vβ_3, with endothelial cell marker FVIII, but not with CD31. Immunostaining for VEGFR-1 and VEGFR-2 additionally co-localized with lineage markers for endothelial progenitor cell and monocytes/macrophages, with a more diverse pattern of co-localization for VEGFR-2.

Conclusion

In a mouse hindlimb ischemia model of peripheral artery disease, [^99mTc]scV SPECT tracer-targeting VEGF receptors showed a more robust signal than [^99mTc]RGD tracer-targeting α_vβ₃. Immunofluorescent analysis suggests that uptake of [^99mTc]scV and [^99mTc]RGD in damaged tissue is due to non-overlapping cell populations and reflects different dynamic processes and that enhanced uptake of [^99mTc]scV may be due to the presence of VEGF receptors on additional cell types.

     

Specific Targeting of Human Integrin α<Subscript>v</Subscript>β<Subscript>3</Subscript> with <Superscript>111</Superscript>In-Labeled Abegrin™ in Nude Mouse Models

Purpose  

The cell adhesion molecule integrin α_vβ₃ is an important player in the process of tumor angiogenesis and metastasis. Abegrin™, a fully humanized anti-integrin α_vβ₃ monoclonal antibody, was currently in clinical trials for cancer therapy. Herein, we labeled Abegrin™ with ¹¹¹In, evaluated the in vitro and in vivo characteristics, and investigated whether the expression of integrin α_vβ₃ in tumors could be imaged with ¹¹¹In-labeled Abegrin™.     

Evaluation of the Microstat™ sublingual PCO<Subscript>2</Subscript> monitor in ambulatory patients

Physicians often need to measure arterial PCO₂ in clinical practice. Arterial blood gas sampling is typically available only in hospitals and may be unpleasant for patients. Minimally invasive techniques for measuring PCO₂ offer the potential for overcoming these limitations. The MicroStat monitor non-invasively measures PCO₂ in the sublingual tissues, which should track arterial PCO₂ in hemodynamically stable patients. This was a prospective observational study. Patients undergoing routine cardiac catheterization were recruited. Following arterial cannulation, two sequential sublingual PCO₂ measurements were taken and a contemporaneous arterial sample was sent for blood gas analysis. For each subject we calculated the mean sublingual–arterial CO₂ gradient and the test–retest sublingual PCO₂ difference. Twenty-five patients were studied. Mean sublingual–arterial PCO₂ gradient was +6.8 mmHg (95 % limits of agreement ?3.0 to 16.6 mmHg). Test–retest difference was 3.4 mmHg (95 % limits of agreement ?1.1 to 7.9 mmHg), p = 0.11 (Wilcoxon test), repeatability was 11 mmHg. The MicroStat sublingual PCO₂ monitor over-estimates arterial PCO₂ with wide limits of agreement. Test–retest repeatability was poor. Use of sublingual PCO2 monitoring with the MicroStat monitor cannot currently replace blood gas sampling.     

Blood Clearance Kinetics,Biodistribution, and Radiation Dosimetry of a Kit-Formulated Integrin α<Subscript>v</Subscript>β<Subscript>3</Subscript>-Selective Radiotracer <Superscript>99m</Superscript>Tc-3PRGD<Subscript>2</Subscript> in Non-Human Primates

Purpose  

^99mTc-3PRGD₂ is a ^99mTc-labeled dimeric cyclic RGD peptide with increased receptor binding affinity and improved kinetics for in vivo imaging of integrin α_vβ₃ expression in nude mouse model. To accelerate its clinical translation, we reported here the evaluation of the kit-formulated ^99mTc-3PRGD₂ in healthy cynomolgus primates for its blood clearance kinetics, biodistribution, and radiation dosimetry.     

Comparison of [<Superscript>99m</Superscript>Tc]3PRGD<Subscript>2</Subscript> Imaging and [<Superscript>18</Superscript>F]FDG PET/CT in Breast Cancer and Expression of Integrin α<Subscript>v</Subscript>β<Subscript>3</Subscript> in Breast Cancer Vascular Endothelial Cells

Purpose

This study aimed to investigate the value of ^99mtechnetium-three polyethylene glycol spacers-arginine-glycine-aspartic acid ([^99mTc]3PRGD₂) imaging in diagnosis and staging of breast cancer compared with 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) imaging, and to explore the expression of integrin α_vβ₃ in tumor vascular endothelial cells.

Procedures

Forty-two women with suspected breast cancer underwent both [^99mTc]3PRGD₂ imaging and [¹⁸F]FDG imaging. Visual analysis was used to assess primary breast lesion, axillary lymph node, and distant metastasis. The tumor-blood (T/B) ratios from [^99mTc]3PRGD₂ imaging and the maximum standardized uptake value (SUVmax) from [¹⁸F]FDG imaging were analyzed for breast lesions. Integrin α_vβ₃ was analyzed through immunohistochemistry.

Results

Forty-five breast lesions were found (malignant, n?=?38; benign, n?=?7). The sensitivity, specificity, and accuracy of [^99mTc]3PRGD₂ and [¹⁸F]FDG imaging in visual analysis for the breast lesion were 97.4, 87.5, and 95.6 % and 97.4, 71.4, and 93.3 %, respectively (P?>?0.05). For semi-quantitative analysis, no significant difference of the area under the curves (AUC) was found in the imaging using the two radiopharmaceuticals (0.880 and 0.955; Z?=?0.88, P?>?0.05). The sensitivity, specificity, and accuracy for axillary lymph node metastasis with [^99mTc]3PRGD₂ and [¹⁸F]FDG were 78.05, 99.36, and 94.92 % and 85.37, 98.72, and 95.64 %, respectively (P?>?0.05). Nine patients with distant metastases were all detected with the two radiopharmaceuticals. The expression of integrin α_vβ₃ was correlated with [^99mTc]3PRGD₂ uptake (r?=?0.582, P?=?0.001), which were significantly higher in the HER2-positive and stage III–IV patients (P?<?0.05).

Conclusions

The prospective study demonstrated that [^99mTc]3PRGD₂ imaging seems to be valuable for diagnosis of breast cancer and its staging. It may be less sensitive for detecting small lymph node metastatic lesions when compared with [¹⁸F]FDG imaging. Integrin α_vβ₃ in tumor microvessels was associated with the breast cancer subtype and its staging.

     

ImmunoPET Imaging of α<Subscript>v</Subscript>β<Subscript>6</Subscript> Expression Using an Engineered Anti-α<Subscript>v</Subscript>β<Subscript>6</Subscript> Cys-diabody Site-Specifically Radiolabeled with Cu-64: Considerations for Optimal Imaging with Antibody Fragments

Purpose

Increased expression of the α_vβ₆ integrin correlates with advanced tumor grade and poor clinical outcome, identifying α_vβ₆ as a prognostic indicator and an attractive target for molecular imaging. This work investigated the ability of a disulfide-stabilized [⁶⁴Cu]NOTA-α_vβ₆ cys-diabody to image α_vβ₆ expression in vivo using a nu/nu mouse model bearing human melanoma xenografts and positron-emission tomography.

Procedures

Small-animal positron emission tomography (PET) imaging, quantitative ROI analysis, and ex vivo biodistribution were conducted to ascertain tumor uptake and organ distribution of the [⁶⁴Cu]NOTA-α_vβ₆ cys-diabody. Immunohistochemical staining of tumors and mouse organs and immunoreactivity assays were utilized to correlate in vivo and ex vivo observations.

Results

PET imaging of the [⁶⁴Cu]NOTA-α_vβ₆ cys-diabody revealed low tumor uptake at 24 h p.i. in DX3Puroβ₆ tumors (2.69 ± 0.45 %ID/g) with comparable results found in the DX3Puro tumors (2.24 ± 0.15 %ID/g). Quantitative biodistribution confirmed that DX3Puroβ₆ tumor uptake was highest at 24 h p.i. (4.63 ± 0.18 %ID/g); however, uptake was also observed in the stomach (4.84 ± 2.99 %ID/g), small intestines (4.50 ± 1.69 %ID/g), large intestines (4.73 ± 0.97 %ID/g), gallbladder (6.04 ± 1.88 %ID/g), and lungs (3.89 ± 0.69 %ID/g).

Conclusions

Small-animal PET imaging was successful in visualizing α_vβ₆-positive tumor uptake of the [⁶⁴Cu]NOTA-α_vβ₆ cys-diabody. Cys-diabody cross-reactivity was observed between human and murine α_vβ₆ and immunohistochemical staining confirmed the presence of an endogenous α_vβ₆ antigen sink, which led to suboptimal tumor contrast in this mouse model. Future investigations will focus on dose escalation studies to overcome the endogenous antigen sink while increasing DX3Puroβ₆ tumor uptake.

     

The venous–arterial difference in CO<Subscript>2</Subscript> should be interpreted with caution in case of respiratory alkalosis in healthy volunteers

The venous–arterial difference in CO₂ (ΔCO₂) has been proposed as an index of the adequacy of tissue perfusion in shock states. We hypothesized that the variation in PaCO₂ (hyper- or hypocapnia) could impact ΔCO₂, partly through microcirculation adaptations. Fifteen healthy males volunteered to participate. For hypocapnia condition (hCO₂), the subjects were asked to hyperventilate, while they were asked to breathe a gas mixture containing 8 % CO₂ for hypercapnia condition (HCO₂). The 2 conditions were randomly assigned. Blood gases were measured at baseline before each condition, and after 5–7 min of either hCO₂ or HCO₂ condition. Microcirculation was assessed by the muscle reoxygenation slope measured with near infrared spectroscopy following a vascular occlusion test and by skin circulation with in vivo reflectance confocal microscopy. ΔCO₂ was significantly increased with hCO₂ while it tended to decrease with HCO₂ (non-significant). HCO₂ induced a moderate increase of the resaturation slope of NIRS oxygenation. Skin microcirculatory blood flow significantly dropped with hCO₂, while it remained unchanged with hypercapnia. Our results warrant cautious interpretation of ΔCO₂ as an indicator of tissue perfusion during respiratory alkalosis.     

Clinicians’ response to hyperoxia in ventilated patients in a Dutch ICU depends on the level of FiO<Subscript>2</Subscript>

Purpose  

Hyperoxia may induce pulmonary injury and may increase oxidative stress. In this retrospective database study we aimed to evaluate the response to hyperoxia by intensivists in a Dutch academic intensive care unit.     

Binding of α<Subscript>v</Subscript>β<Subscript>3</Subscript> Integrin-Specific Radiotracers Is Modulated by Both Integrin Expression Level and Activation Status

Purpose

Molecular imaging of α_vβ₃ integrin has exhibited real potential to guide the appropriate use of anti-angiogenic therapies. However, an incomplete understanding of the factors that influence binding of α_vβ₃ integrin-specific radiotracers currently limits their use for assessing response to therapy in cancer patients. This study identifies two fundamental factors that modulate uptake of these radiotracers.ProceduresExperiments were performed in prostate cancer (PC3) and glioblastoma (U87MG) cells, which differentially express α_vβ₃ integrin. α_vβ₃ integrin-specific radiotracers were used to investigate the effect of manipulating α_vβ₃ integrin expression or activation in cellular binding assays. β₃ integrin and α_vβ₃ integrin expression were measured by western blotting and flow cytometry, respectively. The effect of select pharmacological inhibitors on α_vβ₃ integrin activation and expression was also determined.

Results

Radiotracer binding was proportional to α_vβ₃ integrin expression when it was decreased (β₃ knock-down cells) or increased, either using pharmacological inhibitors of cell signalling or by culturing cells for different times. Studies with both small molecule and arginine–glycine–aspartic acid (RGD)-based radiotracers revealed increased radiotracer binding after activation of α_vβ₃ integrin with Mn²⁺ or talin head domain. Moreover, inhibition of fundamental signalling pathways (mitogen-activated protein kinase kinase (MEK), Src and VEGFR2) decreased radiotracer binding, reflecting reduced α_vβ₃ integrin activity.

Conclusion

Binding of small molecule ligands and radiolabelled RGD peptides is modulated by expression and activation status of α_vβ₃ integrin. α_vβ₃ integrin-specific radiotracers can provide otherwise inaccessible information of the effect of signalling pathways on α_vβ₃ integrin. This has significant implications for assessing response to anti-angiogenic therapies in clinical studies.

     

<Superscript>18</Superscript>F-Labeled Galacto and PEGylated RGD Dimers for PET Imaging of α<Subscript>v</Subscript>β<Subscript>3</Subscript> Integrin Expression

Purpose

In vivo imaging of α_vβ₃ has important diagnostic and therapeutic applications. ¹⁸F-Galacto-arginine–glycine–aspartic acid (RGD) has been developed for positron emission tomography (PET) imaging of integrin α_vβ₃ expression and is now being tested on humans. Dimerization and multimerization of cyclic RGD peptides have been reported to improve the integrin α_vβ₃-binding affinity due to the polyvalency effect. Here, we compared a number of new dimeric RGD peptide tracers with the clinically used ¹⁸F-galacto-RGD.

Procedures

RGD monomers and dimers were coupled with galacto or PEG₃ linkers, and labeled with ¹⁸F using 4-nitrophenyl 2-¹⁸F-fluoropropionate (¹⁸F-NFP) or N-succinimidyl 4-¹⁸F-fluorobenzoate as a prosthetic group. The newly developed tracers were evaluated by cell-based receptor-binding assay, biodistribution, and small-animal PET studies in a subcutaneous U87MG glioblastoma xenograft model.

Results

Starting with ¹⁸F-F^?, the total reaction time for ¹⁸F-FP-SRGD2 and ¹⁸F-FP-PRGD2 is about 120 min. The decay-corrected radiochemical yields for ¹⁸F-FP-SRGD2 and ¹⁸F-FP-PRGD2 are 52?±?9% and 80?±?7% calculated from ¹⁸F-NFP. Noninvasive small-animal PET and direct tissue sampling experiments demonstrated that the dimeric RGD peptides had significantly higher tumor uptake as compared to ¹⁸F-galacto-RGD.

Conclusion

Dimeric RGD peptide tracers with relatively high tumor integrin-specific accumulation and favorable in vivo kinetics may have the potential to be translated into clinic for integrin α_vβ₃ imaging.

     

In vitro performance of prefilled CO<Subscript>2</Subscript> absorbers with the Zeus®

Low fresh gas flows (FGFs) decrease the use of anesthetic gases, but increase CO₂ absorbent usage. CO₂ absorbent usage remains poorly quantified. The goal of this study is to determine canister life of 8 commercially available CO₂ absorbent prepacks with the Zeus^®. Pre-packed CO₂ canisters of 8 different brands were tested in vitro: Amsorb Plus, Spherasorb, LoFloSorb, LithoLyme, SpiraLith, SpheraSorb, Drägersorb 800+, Drägersorb Free, and CO2ntrol. CO₂ (160 mL min^??1) flowed into the tip of a 2 L breathing bag that was ventilated with a tidal volume of 500 mL, a respiratory rate of 10/min, and an I:E ratio of 1:1 using the controlled mechanical ventilation mode of the Zeus^® (Dräger, Lubeck, Germany). In part I, canister life of 5 canisters each of 2 different lots of each brand was determined with a 350 mL min^??1 FGF. Canister life is the time it takes for the inspired CO₂ concentration (F_ICO₂) to rise to 0.5%. In part II, canister life was measured accross a FGF range of 0.25 to 4 L min^??1 for Drägersorb 800+ (2 lots) and SpiraLith (1 lot). In part III, the calculated canister life per 100 g fresh granule content of the different brands was compared between the Zeus and (previously published data for) the Aisys. In vitro canister life of prefilled CO₂ absorber canisters differed between brands, and depended on the amount of CO₂ absorbent and chemical composition. Canister life expressed as FCU_0.5 (the fraction of the canister used per hour) was proportional to FGF over 0.2–2 L min^?1 range only, but was non-linear with higher FGF: FCU_0.5 was larger than expected with FGF?>?2 L min^?1, and even with FGF?>?minute ventilation FCU_0.5 did not become zero, indicating some CO₂ was being absorbed. Canister life on a per weight basis of the same brand is higher with the Zeus than the Aisys. Canister life of prefilled CO₂ absorber canisters differs between brands. The FCU_0.5–FGF relationship is not linear across the entire FGF range. Canister life of prepacks of the same brand for the Zeus and Aisys differs, the exact etiology of which is probably multifactorial, and may include differences in the absolute amount of absorbent and different rebreathing characteristics of the machines.     

Do changes in pulse oximeter oxygen saturation predict equivalent changes in arterial oxygen saturation?

Introduction  

This study investigates the relation between changes in pulse oximeter oxygen saturation (SpO ₂) and changes in arterial oxygen saturation (SaO ₂) in the critically ill, and the effects of acidosis and anaemia on precision of using pulse oximetry to predict SaO ₂.     

In vitro performance of prefilled CO<Subscript>2</Subscript> absorbers with the Aisys<Superscript>®</Superscript>

Low flow anesthesia increases the use of CO₂ absorbents, but independent data that compare canister life of the newest CO₂ absorbents are scarce. Seven different pre-packed CO₂ canisters were tested in vitro: Amsorb Plus, Spherasorb, LoFloSorb, Medisorb, Medisorb EF, LithoLyme, and SpiraLith. CO₂ (160 mL min^?1) flowed into the tip of a 2 L breathing bag that was ventilated with a tidal volume of 500 mL, a respiratory rate of 10/min, and an I:E ratio of 1:1 using the controlled mechanical ventilation mode of the Aisys ^® (GE, Madison, WI, USA). In part I, canister life of each brand (all of the same lot) was tested with 12 different fresh gas flows (FGF) ranging from 0.25 to 4 L min^?1. In part II, canister life of six canisters each of two different lots of each brand were tested with a 350 mL min^?1 FGF. Canister life is presented as “FCU”, fractional canister usage, the fraction of a canister used per hour, and is defined for the inspired CO₂ concentration (F_ICO₂) that denotes exhaustion. In part III, canister life per 100 g fresh granule content was calculated. FCU decreased linearly with increasing FGF. The relative position of the FCU–FGF curves of the different brands depends on the F_ICO₂ threshold because the exhaustion rate (the rate of rise once F_ICO₂ starts to increase) differs among the brands. Intra-lot variability was 18 % or less. The different prepacks can be ranked according their efficiency (least to most efficient) as follows: Amsorb Plus = Medisorb EF < LoFloSorb < Medisorb = Spherasorb = LithoLyme < SpiraLith (all for an F_ICO₂ threshold = 0.5 %). Canister life per 100 g fresh granule content is almost twice as long when LiOH is used as the primary absorbent. The most important factors that determine canister life of prepacks in a circle breathing system are the chemical composition of the canister, the absolute amount of absorbent present in the canister, and the F_ICO₂ replacement threshold. The use of the fractional canister usage allows cost comparisons among different prepacks. Results should not be extrapolated to prepacks that fit onto other anesthesia machines.     

The Arg389Gly β<Subscript>1</Subscript>-adrenoceptor gene polymorphism influences the acute effects of β-adrenoceptor blockade on contractility in the human heart

Background  

The β₁-adrenoceptor (β₁AR) mediates cardiostimulatory effects of catecholamines in the heart. The Arg389Gly polymorphism of the β₁AR gene has recently been shown to determine the responsiveness to catecholamines in vitro, and we previously reported that dobutamine induced an augmented contractile response in humans homozygous for the Arg389 allele. The aim of the present study was to evaluate whether the Arg389Gly β₁AR gene polymorphism influences the responsiveness to β-blocker treatment on cardiac contractility.     

Continuous monitoring of ScvO<Subscript>2</Subscript> by a new fibre-optic technology compared with blood gas oximetry in critically ill patients: a multicentre study

Objective The aim of this study was to compare the accuracy of the CeVOX monitor measuring continuous central venous saturation (ScvO₂) with laboratory blood gas oximetry under clinical circumstances. Design Prospective, multicentre, observational study. Setting Five adult general intensive care units. Patients and participants Fifty-three critically ill patients. Interventions The fibre-optic probe was inserted into an ordinary central venous catheter's distal lumen. Blood samples were taken from this line via a Y-adapter every 8 h and ScvO₂ was measured with a laboratory co-oximeter. Patients were observed for a maximum of 5 days. Results were compared using linear regression and the Bland and Altman plots. Measurements and results The 526 matched pairs of ScvO₂ showed a significant correlation between the two methods (r = 0.79, p< 0.001). Bland–Altman plots showed an overall mean bias of –0.3% and moderate agreement (lower and upper levels of agreement: –13.2% and 12.5%). Correlation for the first time point, and for differences between the first two time points for each method revealed good correlation: (n = 53): r = 0.79, p< 0.001; (n = 50): r = 0.58, p< 0.001, respectively. Conclusion These results in a heterogeneous group of critically ill patients show that continuous ScvO₂ monitoring by the CeVOX technology yielded results comparable with those obtained by laboratory co-oximetry and therefore can be relied on in everyday clinical practice. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Nitroglycerin‐induced changes in facial skin temperature: ‘cold nose’ as a predictor of headache?

Nitroglycerin (NTG) often induces headaches when used to treat cardiac diseases. Such property of NTG has been widely used in modelling of migraine‐like headaches. However, background reasons, predisposing to the development of NTG‐headache, are less studied. The main aim of our study was to find, using NTG model, easily accessible markers of the vascular changes associated with headache. Because changes in the blood flow alter the local skin temperature (Tsk), we studied the relationship between the regional changes in the facial Tsk and NTG‐induced headaches. Tsk was measured with infrared thermography in 11 healthy women during 3 h after sublingual NTG administration. NTG caused headache in five women, and four of them were the first‐degree relatives of migraine patients. Notably, before NTG administration, subjects in the headache group had lower Tsk values, especially in the nose area, than women in the pain‐free group (n = 6). NTG‐induced headache was associated with a long‐lasting increase of Tsk over the baseline. In sharp contrast, in the pain‐free group, the Tsk reduced and returned rapidly to the baseline. Thus, the low baseline level and greater increase of regional Tsk correlated with the incidence of headache that supports a role of greater vascular changes in headache happening on the basis of the dissimilarities in vascular tone. An easily accessible phenomenon of ‘cold nose’ may indicate background vascular dysfunctions in individuals with predisposition to headache. Facial infrared thermography, coupled with NTG administration, suggests a novel temporally controlled approach for non‐invasive investigation of vascular processes accompanying headaches.     

Can changes in arterial pressure be used to detect changes in cardiac index during fluid challenge in patients with septic shock?

Purpose  

Response to fluid challenge is often defined as an increase in cardiac index (CI) of more than 10–15%. However, in clinical practice CI values are often not available. We evaluated whether changes in mean arterial pressure (MAP) correlate with changes in CI after fluid challenge in patients with septic shock.