H2 inhalation therapy in patients with moderate COVID-19 (H2COVID): a prospective ascending-dose phase I clinical trial.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has triggered a serious global health crisis, resulting in millions of reported deaths since its initial identification in China in November 2019. The global disparities in immunization access emphasize the urgent need for ongoing research into therapeutic interventions. This study focuses on the potential use of molecular dihydrogen (H2) inhalation as an adjunctive treatment for COVID-19. H2 therapy shows promise in inhibiting intracellular signaling pathways associated with inflammation, particularly when administered early in conjunction with nasal oxygen therapy. This phase I study, characterized by an open-label, prospective, monocentric, and single ascending-dose design, seeks to assess the safety and tolerability of the procedure in individuals with confirmed SARS-CoV-2 infection. Employing a 3 + 3 design, the study includes three exposure durations (target durations): 1 day (D1), 3 days (D2), and 6 days (D3). We concluded that the maximum tolerated duration is at least 3 days. Every patient showed clinical improvement and excellent tolerance to H2 therapy. To the best of our knowledge, this phase I clinical trial is the first to establish the safety of inhaling a mixture of H2 (3.6%) and N2 (96.4%) in hospitalized COVID-19 patients. The original device and method employed ensure the absence of explosion risk. The encouraging outcomes observed in the 12 patients included in the study justify further exploration through larger, controlled clinical trials. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04633980.

Direct admission of stroke in MRI room reduces in-hospital delays and improves recovery.

PURPOSE: Efficacy of intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) is strongly time dependent in acute stroke management. We investigated the impact of a direct magnetic resonance imaging (MRI) room admission protocol in order to reduce in-hospital delays. METHODS: We implemented a protocol of direct MRI room admission, bypassing the Emergency Department. We compared in-hospital delays, clinical and functional outcomes using National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores, between patients hospitalized via this protocol and those admitted via the standard workflow and treated by IVT and/or MT. The primary endpoint was the proportion of patients with door-to-needle time (DTN) ≤ 60minutes. RESULTS: Among 308 consecutive patients included, 62 underwent direct MRI room admission. The proportion of patients with DTN ≤ 60minutes was higher in the intervention group compared to the control group (82.5% vs. 17.8%, P<0.001), and median DTN was lower (45min vs. 75min, P<0.001). Despite a functional benefit at discharge on dichotomized mRS (mRS [0-2, as independence]: 66.1% vs. 51.2%, P=0.003), the difference was no longer statistically significant at six months (68.4% vs. 57.4%, P=0.10). CONCLUSION: Direct MRI room admission of stroke alerts is associated with an important reduction of treatment times and improves functional outcomes.

Assessment of linezolid prescriptions in three French hospitals.

The use of linezolid to treat gram-positive cocci infections is increasing in France. Linezolid is approved in pneumonia and complicated skin and soft tissue infections. Overuse and misuse of linezolid can favor the emergence and spreading of linezolid-resistant strains. We aimed to assess the appropriateness of linezolid use in French hospitals. This is a multicenter, retrospective study conducted in three tertiary care hospitals. Appropriateness of linezolid indications and adequacy (composite score concerning dosage, route of administration and blood monitoring) were assessed. Over a three-month period, all prescriptions of linezolid were extracted and analyzed by two independent infectious disease experts. Among the 81 initial prescriptions that were evaluated, indication was appropriate in 48% of cases. Among those, 51% complied with international guidelines. Fifty-seven percent of the prescriptions were adequate regarding dosage, route of administration and blood monitoring. Overall, 23% of prescriptions combined both appropriateness and adequacy. The most frequent reasons for inappropriateness were the possibility of choosing narrower-spectrum antibiotics and the empirical use of linezolid in severe sepsis or septic shock. Initial treatment was the most frequently appropriate in bone and joint infection cases (p = 0.001). Our study shows that even if modalities of use were mostly correct, appropriateness of linezolid indications is low. Educational programs are mandatory to improve practices, as well as clinical studies to better assess the efficacy and safety of linezolid in clinical situations other than pneumonia or complicated skin and soft tissue infections.

Recurrent peripheral vestibulopathy: Is MRI useful for the diagnosis of endolymphatic hydrops in clinical practice?

OBJECTIVES: Recurrent peripheral vestibulopathy (RPV) is a public health problem, yet the aetiology remains unclear. Recent developments in MRI of endolymphatic hydrops (EH) allow for a better understanding of inner ear disorders. We intended to study the prevalence of EH in patients with RPV, in comparison to those with Meniere's disease (MD). METHODS: MRI examinations were performed 4 hours after intravenous injection of gadoteric acid in 132 patients with RPV (n = 64) and MD (n = 68). Two radiologists retrospectively studied the prevalence and localization of EH in RPV and MD groups. Patients were graded based on the number and localization of hydrops, between 1 (EH in either cochlea or vestibule on one side) and 4 (EH in cochlea and vestibule on both ears). RESULTS: We identified EH in 31 out of 64 patients and in 61 out of 68 patients in the RPV and MD groups, respectively. There was a significant difference regarding the number of subjects with EH between the two groups (p ≤ 0.01), with a higher average number of hydrops localization in MD group (p ≤ 0.01). CONCLUSION: MRI may reveal EH in some cases among patients with RPV, suggesting a similar pathophysiological mechanism in comparison with MD. KEY POINTS: • MRI may reveal endolymphatic hydrops in some patients with recurrent peripheral vestibulopathy. • We suggest a similar pathophysiological mechanism in recurrent vestibulopathy and Meniere's Disease. • MRI with delayed acquisition helps clinicians to assess patients with recurrent vestibulopathy. • The outcome would be to aid the development of adapted therapeutic strategies. • MRI of endolymphatic hydrops should probably be included in future diagnostic protocols.

The digital thermal hyperemia pattern is associated with the onset of digital ulcerations in systemic sclerosis during 3 years of follow-up.

OBJECTIVES: One of the most important skin complications in systemic sclerosis (SSc) is digital ulceration. Local thermal hyperemia (LTH) in the skin is a biphasic response to local heating involving both neurovascular and endothelial responses. Since LTH is abnormal in SSc patients, we aimed at testing whether LTH could be a prognostic tool for the onset of digital ulcers. METHODS: We prospectively enrolled 51 patients with SSc. Nailfold capillaroscopy and LTH were recorded at baseline, and patients were followed for 3 years. RESULTS: No patient with a LTH peak/plateau ratio ≥1 (n=19) developed digital ulcerations during the 3 year follow-up (100% negative predictive value), while 6 out of 32 patients with a LTH peak/plateau ratio <1 at enrolment presented with finger pad ulcerations within 3 years (p=0.05). In contrast, when lidocaine/prilocaine was applied to the finger pad, no relationship between thermal hyperemia and digital ulcerations was observed. CONCLUSIONS: A LTH peak/plateau ratio on the finger pad greater than 1, which can easily be determined in routine clinical practice, could be used to reassure patients, whatever the subtype of SSc, about the low probability of future digital ulceration. However, the prognostic value of this parameter should be confirmed in a larger cohort.

Abnormal amplitude and kinetics of digital postocclusive reactive hyperemia in systemic sclerosis.

OBJECTIVES: Postocclusive reactive hyperemia is mediated by two major mediators: sensory nerves and endothelium-derived hyperpolarizing factors. We hypothesized that the skin microvascular response to 5 min ischemia would differ depending upon the hand location in patients with systemic sclerosis (SSc), primary Raynaud's phenomenon (PRP) and healthy controls. METHODS: Fifteen patients with SSc, 15 sex- and age-matched patients with PRP and healthy controls were enrolled. Their right hands were subjected to 5 min ischemia followed by a postocclusive hyperemia test, with local microcirculation monitoring by laser speckle contrast imaging on the dorsal face of the hand. RESULTS: Postocclusive reactive hyperemia was abnormal in terms of peak and area under the curve (AUC) on all fingers except the thumb in patients with SSc and PRP compared with controls. In contrast, the kinetics of the response was longer only in SSc patients, with mean (SD) time to peak on the index, middle and ring finger were respectively 72 (58), 73 (51) and 67 (47) s for SSc; 40 (20), 40 (20) and 36 (19) s for PRP; and 34 (30), 34 (30) and 29 (24) s for controls (P=0.009 for interaction). CONCLUSIONS: We observed decreased distal digital microvascular perfusion following 5 min of ischemia in patients presenting with PRP or SSc, while the kinetics was prolonged only in SSc. A dynamic assessment of digital skin blood flow using laser speckle contrast imaging following 5 min ischemia could be used as a tool to assess microvascular abnormalities in patients with Raynaud's phenomenon secondary to SSc.

[How can we evaluate medication adherence? What are the methods?]. / Comment évaluer l'adhésion médicamenteuse? Le point sur les méthodes.

INTRODUCTION: Identifying the difficulties of the patient towards following his medication regimen remains complex for the healthcare provider. This can be explained by the multidimensional character of medication adherence and, actually, the evaluation of this phenomenon. The objective of this work was to review the various methods to measure medication adherence. METHODS: We performed a search on PubMed completed by a manual one. RESULTS: Two types of measure are described. The "direct" methods are based on the measurement of the level of medicine or metabolite in blood or urine, measurement of biologic markers in blood or measurement of physiologic or clinical markers. The "indirect" methods are represented by the analysis of the administrative databases (prescription, rate of prescription refills); pill counts; electronic medication monitors; the self-reported measures by the patient or his close relations (questionnaires, diaries, interviews); the opinion of the healthcare provider. DISCUSSION: None of these tools supplants the others, each having limits either of feasibility, or reliability. In the end, it is the crossing of the information stemming from these various equipments that allows an idea on the adherence behavior of the patient and especially, dimensions on which he is most in trouble. CONCLUSION: The identification of these difficulties can allow the healthcare provider to develop behavioral and organizational skills tailored to the patient follow-up.

Comparison between laser speckle contrast imaging and laser Doppler imaging to assess skin blood flow in humans.

OBJECTIVE: We tested the linearity between skin blood flux recorded with laser speckle contrast imaging (LSCI) and laser Doppler imaging (LDI), comparing different ways of expressing data. A secondary objective was to test within-subject variability of baseline flux with the two techniques. METHODS: We performed local heating at 36, 39, 42, and 44°C on the forearm of healthy volunteers, and measured cutaneous blood flux with LDI and LSCI. Biological zero (BZ) was obtained by occluding the brachial artery. We expressed data as raw arbitrary perfusion units (APUs) and as a percentage increase from baseline (%BL), with and without subtracting BZ. Inter-site variability was expressed as a within subject coefficient of variation (CV). RESULTS: Twelve participants were enrolled. Inter-site variability at baseline was lower with LSCI (CV=9.2%) than with LDI (CV=20.7%). We observed an excellent correlation between both techniques when data were expressed as raw APUs or APU-BZ (R=0.90; p<0.001). The correlation remained correct for %BL (R=0.77, p<0.001), but decreased for %BL-BZ (R=0.44, p=0.003). Bland-Altman plots revealed a major proportional bias between the two techniques. CONCLUSION: This study suggests that skin blood flux measured with LSCI is linearly related to the LDI signal over a wide range of perfusion. Subtracting BZ does not affect this linearity but introduces variability in baseline flux, thus decreasing the correlation when data are expressed as a function of baseline. Finally, systematic bias makes it impossible to assimilate arbitrary perfusion units provided by the two systems.

Sample entropy of laser Doppler flowmetry signals increases in patients with systemic sclerosis.

Associated to reactivity tests, laser Doppler flowmetry (LDF) emphasizes abnormal skin microvascular function in diseases affecting digits, such as Raynaud's phenomenon (RP) and systemic sclerosis (SSc). However, baseline perfusion value does not discriminate between disease states. We study if LDF sample entropy (SampEn) allows distinguishing healthy subjects, RP and SSc patients. LDF measurements were performed on finger pad and forearm of 108 subjects (27 controls, 28 RP patients, 53 SSc patients), before and after local thermal hyperemia. We also assessed the reproducibility of SampEn [expressed as within-subject coefficients of variation (CV) and intra-class correlation coefficients (ICC)]. Baseline SampEn is significantly increased in patients with SSc compared to RP and controls on finger pad [0.49 (0.19), 0.38 (0.14) and 0.36 (0.15), respectively; P<0.002], but not on forearm. However, local thermal hyperemia increased SampEn at all sites and for all groups. Finally, reproducibility of SampEn computed on two baseline segments was acceptable (CV=26%, ICC=0.63). SampEn of skin blood flow at rest is increased on finger pad of patients with SSc but not on forearm. This is consistent with the pathophysiology of the disease, which predominantly affects digital microcirculation in most patients. SampEn of LDF signal could be a reproducible tool to predict digital microvascular impairment.

Skin microdialysis coupled with laser speckle contrast imaging to assess microvascular reactivity.

OBJECTIVE: Laser speckle contrast imaging (LSCI) can be used to assess real-time responses of skin microcirculation to pharmacological interventions. The main objective of this study was to determine whether intradermal or subdermal microdialysis fiber insertion, coupled with skin flux recording using LSCI, can be used to assess baseline cutaneous flux and the post-occlusive reactive hyperemic response. The microdialysis sites were compared to control area without microdialysis fibers. METHODS: One dermal and two subdermal microdialysis fibers were randomly inserted in the right forearm skin of six healthy volunteers. We performed consecutively tests of post-occlusive hyperemia, infusion of 29 mM sodium nitroprusside (SNP), local thermal hyperemia at 43°C and a second 29 mM SNP infusion at the end of the experiment. RESULTS: Two hours after fiber insertion, cutaneous vascular conductances (CVC) at the subdermal fiber sites were not different from their respective control regions of interest, while at the dermal site CVC remained higher (0.48+/-0.15 versus 0.37+/-0.1 PU.mm Hg(-1), P=0.003). The peak CVC and area under the curve observed during post-occlusive reactive hyperemia were similar at all fiber sites and their respective controls. We observed a similar increase in CVC using 29 mM SNP infusion, 40 min local heating at 43°C, and their combination. Finally, physiological and pharmacological responses of the subdermal sites were reproducible in terms of amplitude, whether expressed as raw CVC or as % CVCmax. CONCLUSIONS: We showed that studying skin microvascular physiological or pharmacological responses using inserted subdermal microdialysis fibers coupled with LSCI is feasible and reproducible, and provides two-dimensional information. This technique will be useful for future mechanistic studies of skin microcirculation.

Management of voriconazole hepatotoxicity in a lung transplant patient.

Lung allograft airway colonization by Aspergillus species is common among lung transplant recipients. We report the case of a 46-year-old female lung transplant outpatient diagnosed with persistent pulmonary Aspergillus colonization (>50 colonies of Aspergillus terreus) 3 months after lung transplantation. Oral voriconazole 200 mg twice a day (b.i.d) was initiated shortly after diagnosis. Two days after voriconazole initiation, alkaline phosphatase (ALP), alanine transaminase (ALT), and aspartate transaminase (AST) were normal or slightly elevated (79, 37, and 21 UI/L, respectively). Ten days after the first voriconazole administration, these values started to increase. Maximum levels were reached after 20 days for ALP (369 UI/L) and at around 30 days for ALT and AST (223 and 188 UI/L, respectively). Instead of discontinuing antifungal therapy, it was decided to reduce the voriconazole dose to 100 mg b.i.d. This asymptomatic progressive cholestatic hepatitis resolved, and 10 days after dose reduction ALP, ALT, AST were at 136, 53, and 28 UI/L, respectively. Finally, therapeutic drug monitoring revealed adequate voriconazole plasma trough concentrations (0.98 mg/L) 30 days after dose reduction and no more colonies of Aspergillus were observed. Voriconazole-induced hepatotoxicity is a well known dose-dependent adverse drug reaction. This experience confirms the appropriateness of voriconazole dose reduction instead of therapy interruption in dose-dependent moderate liver toxicity. Voriconazole therapeutic drug monitoring before and after dose reduction may help to avoid drug accumulation and inappropriately low drug exposure, respectively.

Reproducibility and methodological issues of skin post-occlusive and thermal hyperemia assessed by single-point laser Doppler flowmetry.

OBJECTIVE: The primary objective of this study was to evaluate 1-week reproducibility of post-occlusive reactive hyperemia (PORH) and local thermal hyperemia (LTH) assessed by single-point laser-Doppler flowmetry (LDF) on different skin sites. We also evaluated spatial reproducibility of both tests on the forearm. Finally, we assessed the influence of mental stress and room temperature variations on PORH and LTH. METHODS: We performed PORH and LTH assessing skin blood flow on the forearm and on the finger pad with LDF. We repeated the sequence 1 week later. We also performed PORH and LTH during mental stress (Stroop test) and at room temperatures of 21 degrees C and 27 degrees C. Data were expressed as cutaneous vascular conductance (CVC), as a function of baseline and as a function of 44 degrees C vasodilation (%CVC(44)). Reproducibility was expressed as within subject coefficients of variation (CV) and intra-class correlation coefficients (ICC). RESULTS: Fourteen Caucasian healthy volunteers were recruited. Median age was 25 (2.7) and 50% were female. Median body mass index was 21.2 (5). PORH was reproducible on the finger, whether expressed as raw CVC (CV=25%; ICC=0.56) or as %CVC(44) (CV=24%; ICC=0.60). However, PORH showed poor reproducibility on the forearm. In the same way, LTH was reproducible on the finger pad when expressed as CVC (CV=17%; ICC=0.81) but not on the forearm. Spatial reproducibility was poor on the forearm. Elevated room temperature (27 degrees C) affected PORH and LTH on the finger pad (p<0.05) but not on the forearm. CONCLUSION: Single-point LDF is a reproducible technique to assess PORH and LTH on the finger pad when data are expressed as raw CVC or %CVC(44). On the forearm, however, it shows great inter-day variability, probably due to spatial variability of capillary density. These results highlight the need for alternative techniques on the forearm.

Excellent reproducibility of laser speckle contrast imaging to assess skin microvascular reactivity.

OBJECTIVE: We compared the inter-day reproducibility of post-occlusive reactive hyperemia (PORH) assessed by single-point laser Doppler flowmetry (LDF) and laser speckle contrast analysis (LSCI), and the reproducibility of local thermal hyperemia (LTH) assessed by LDF, laser Doppler imaging (LDI) and LSCI. We also tested whether skin blood flow assessment by LDF and by LSCI are correlated. METHODS: Skin blood flow was evaluated during PORH and LTH using LDF, LDI (for LTH only) and LSCI on the forearms of healthy volunteers, at a 7day interval. Data are expressed as cutaneous vascular conductance (CVC), as a function of baseline and scaled to the thermal plateau. Reproducibility is expressed as within subject coefficients of variation (CV, in %) and intra-class correlation coefficients (ICC). RESULTS: Twenty-eight healthy participants were enrolled in this study. The reproducibility of the PORH peak CVC was better when assessed with LSCI compared to LDF (CV=8%; ICC=0.76 and CV=30%; ICC=0.54, respectively). Inter-day reproducibility of the LTH plateau was better when assessed with LSCI or LDI than LDF (CV=15%, ICC=0.66; CV=17%, ICC=0.51 and CV=42%, ICC=0.28 respectively). Finally, we observed significant correlation between simultaneous LDF and LSCI measurements of the PORH peak CVC (R=0.54; p=0.001). CONCLUSION: The recently developed LSCI technique showed very good inter-day reproducibility for assessing PORH and LTH. Moreover, we showed significant correlation between LSCI and single-point LDF for PORH. However, more data are needed to evaluate the linearity between the LSCI signal and skin blood flow.

Reproducibility of a local cooling test to assess microvascular function in human skin.

OBJECTIVE: In the present study we aimed to assess the reproducibility of skin microvascular reactivity while fast cooling locally with a custom-designed laser-Doppler flowmetry (LDF) probe. METHODS: Twenty-two healthy volunteers underwent local 15 degrees C cooling on the forearm during 5 (protocol 1, n=12) or 30 min (protocol 2, n=10). Skin blood flow was concomitantly assessed using LDF. Measurements were repeated after 30 min (protocol 1) or 7 days (protocols 1 and 2). Data were expressed as cutaneous vascular conductance (CVC) and percentage of baseline (%BL). Within subject coefficients of variation (CV) and intra-class correlation coefficients (ICC) were calculated. RESULTS: Immediate reproducibility of the 5-min cooling was very good, either expressed as CVC or %BL (CV were 8% and 18%; ICC were 0.85 and 0.78, respectively). However, the 30-min cooling was the most reproducible at 1 week, either as CVC or %BL (CV were 26% and 23%; ICC were 0.86 and 0.75, respectively). Local cooling was well tolerated by all volunteers. CONCLUSIONS: We propose in the present work a reproducible 30-min LDF cooling test. Such a tool could be of great interest to assess microvascular reactivity to local cooling in diseases such as Raynaud's syndrome, and to further evaluate drugs for such diseases.

Chloroquine and hydroxychloroquine in the management of COVID-19: Much kerfuffle but little evidence.

Chloroquine and hydroxychloroquine are drugs that have shown in vitro activity on the replication of certain coronaviruses. In the context of the SARS-Cov-2 epidemic, the virus responsible for the novel coronavirus disease (COVID-19), these two drugs have been proposed as possible treatments. The results of the first clinical studies evaluating the effect of hydroxychloroquine do not support any efficacy of this drug in patients with COVID-19, due to major methodological weaknesses. Yet, these preliminary studies have aroused considerable media interest, raising fears of massive and uncontrolled use. In the absence of evidence of clinical benefits, the main risk is of exposing patients unnecessarily to the well-known adverse effects of hydroxychloroquine, with a possibly increased risk in the specific setting of COVID-19. In addition, widespread use outside of any recommendation risks compromising the completion of good quality clinical trials. The chloroquine hype, fueled by low-quality studies and media announcements, has yielded to the implementation of more than 150 studies worldwide. This represents a waste of resources and a loss of opportunity for other drugs to be properly evaluated. In the context of emergency, rigorous trials are more than ever needed in order to have, as soon as possible, reliable data on drugs that are possibly effective against the disease. Meanwhile, serious adverse drug reactions have been reported in patients with COVID-19 receiving hydroxychloroquine, justifying to limit its prescription, and to perform suitable cardiac and therapeutic drug monitoring.

Sodium nitroprusside iontophoresis on the finger pad does not consistently increase skin blood flow in healthy controls and patients with systemic sclerosis.

OBJECTIVE: Sodium nitroprusside (SNP) iontophoresis is a commonly used technique to assess non endothelium-dependent skin microvascular function in the forearm. However, the lack of data on the finger pad is a limitation when studying diseases affecting the digits (e.g. systemic sclerosis, SSc). We thus aimed to validate this technique in the finger pad compared to the forearm in SSc patients and healthy controls. METHODS: Six SSc patients and six controls were recruited. SNP and NaCl iontophoresis were performed on the finger pad and the forearm, with and without lidocaine/prilocaine. Cutaneous blood flow was simultaneously monitored using laser Doppler flowmetry. RESULTS: In all subjects, iontophoresis of SNP induced hyperemia in the forearm, which was not affected by pretreatment with lidocaine/prilocaine. In contrast, no increase in cutaneous vascular conductance was observed in the finger pad in any subject (apart from one patient with SSc). CONCLUSIONS: The iontophoresis of SNP leads to a consistent, non axon reflex-dependent, increase in cutaneous vascular conductance in the forearm, both in patients with SSc and in healthy controls. On the finger pad however, such hyperemia was not consistent. As a consequence, other tools should be considered to assess non endothelium-dependent skin microvascular function in the finger pad.

Leukotriene B4: early mediator of atherosclerosis in obstructive sleep apnoea?

Severity of oxygen desaturation is predictive of early atherosclerosis in obstructive sleep apnoea (OSA). Leukotriene (LT)B(4) is a lipid mediator involved in atherogenesis. In 40 non-obese OSA patients, free of a cardiovascular history, and 20 healthy volunteers, the following were evaluated: 1) LTB(4) production by polymorphonuclear leukocytes (PMNs) stimulated with A23187; and 2) the relationships between LTB(4) production and both OSA severity and infraclinical atherosclerosis markers. The effect of continuous positive airway pressure (CPAP) on LTB(4) production was also studied. An overnight sleep study was followed by first-morning blood sampling. Isolated PMNs were stimulated with A23187 in order to induce LTB(4) production, which was measured by liquid chromatography-tandem mass spectrometry. Carotid intima-media thickness (IMT) and luminal diameter were measured in subset groups of 28 OSA patients and 11 controls. LTB(4) production was increased in OSA patients compared with controls. LTB(4) levels correlated with the mean and minimal arterial oxygen saturation (S(a,O(2))). LTB(4) production correlated with luminal diameter data in patients with a mean S(a,O(2)) of < or = 94% but not with IMT. Lastly, CPAP significantly reduced LTB(4) production by 50%. Leukotriene B(4) production is increased in obstructive sleep apnoea in relation to oxygen desaturation. Leukotriene B(4) could promote early vascular remodelling in moderate-to-severe hypoxic obstructive sleep apnoea patients.

Abnormal digital neurovascular response to local heating in systemic sclerosis.

OBJECTIVES: To investigate neurovascular dysfunction using the axon reflex-dependent hyperaemia (initial peak of skin local heating response) in fingers of patients with SSc or primary RP. METHODS: Ten healthy subjects were initially enrolled to compare axon reflex-dependent thermal hyperaemia between the finger and forearm cutaneous circulations. Then, 10 patients with primary RP and 16 patients with SSc participated in a similar protocol focusing on the finger circulation only. Lidocaine/prilocaine cream was applied for 1 h to produce local blockade of cutaneous sensory nerves. After lidocaine/prilocaine pre-treatment, laser Doppler probes were heated from skin temperature to 42 degrees C for 30 min, and 44 degrees C for 5 min to achieve maximal skin blood flow. Data were expressed as a percentage of maximal cutaneous vascular conductance. RESULTS: In healthy volunteers, we observed a significantly higher initial peak on the finger compared with the forearm, with both responses blunted following topical anaesthesia. In primary RP patients, we observed a decreased initial peak following lidocaine/prilocaine pre-treatment in the finger circulation [96.7% (33.4) vs 75.9% (29.5) with anaesthesia, P = 0.02]. In contrast, pre-treatment did not alter the initial peak in patients with SSc. A minute-by-minute analysis showed no delay of the initial peak. CONCLUSIONS: We show an abnormal digital neurovascular response to local heating in SSc. Thermal hyperaemia could be monitored as a clinical test for neurovascular function in SSc. Further studies are required to test whether the abnormal digital neurovascular response correlates to the degree of peripheral vascular involvement.

Cutaneous iontophoresis of treprostinil in systemic sclerosis: a proof-of-concept study.

Ischemic digital ulcer (DU) is a serious complication of systemic sclerosis (SSc). Intravenous prostanoids are the only approved treatment for active DUs, but they induce dose-limiting side effects and require hospitalization. Our objective was to evaluate the effect of iontophoresis (a noninvasive drug delivery method) of treprostinil in SSc patients. Three studies were conducted: a pharmacokinetic study in 12 healthy volunteers showed that peak dermal concentration was reached at 2 hours, whereas plasma treprostinil was undetected. Then, a placebo-controlled, double-blind incremental dose study assessed the effect of treprostinil on digital skin blood flow in 22 healthy subjects. The effect of the highest dose was then compared with that of placebo in 12 SSc patients. Treprostinil significantly increased skin blood flow in healthy subjects (P = 0.006) and in SSc patients (P = 0.023). In conclusion, digital iontophoresis of treprostinil is feasible, is well tolerated, and increases digital skin perfusion. It could be tested as a treatment for SSc-related DUs.