Aims: To test the acute hemodynamic effect of acetazolamide in patients with pulmonary hypertensi... more Aims: To test the acute hemodynamic effect of acetazolamide in patients with pulmonary hypertension (PH) under ambient air and hypoxia. Methods: Patients with pulmonary arterial or chronic thromboembolic PH (PAH/CTEPH) undergoing right heart catheterization were included in this randomized, placebo-controlled, double-blinded, crossover trial. The main outcome, pulmonary vascular resistance (PVR), further hemodynamics, blood-and cerebral oxygenation were measured 1 h after intravenous administration of 500 mg acetazolamide or placebo-saline on ambient air (normoxia) and at the end of breathing hypoxic gas (F I O 2 0.15, hypoxia) for 15 min. Results: 24 PH-patients, 71% men, mean ± SD age 59 ± 14 years, BMI 28 ± 5 kg/m 2 , PVR 4.7 ± 2.1 WU participated. Mean PVR after acetazolamide vs. placebo was 5.5 ± 3.0 vs. 5.3 ± 3.0 WU; mean difference (95% CI) 0.2 (−0.2-0.6, p = 0.341). Heart rate was higher after acetazolamide (79 ± 12 vs. 77 ± 11 bpm, p = 0.026), pH was lower (7.40 ± 0.02 vs. 7.42 ± 0.03, p = 0.002) but PaCO 2 and PaO 2 remained unchanged while cerebral tissue oxygenation increased (71 ± 6 vs. 69 ± 6%, p = 0.017). In acute hypoxia, acetazolamide decreased PVR by 0.4 WU (0.0-0.9, p = 0.046) while PaO 2 and PaCO 2 were not changed. No adverse effects occurred. Conclusions: In patients with PAH/CTEPH, i.v. acetazolamide did not change pulmonary hemodynamics compared to placebo after 1 hour in normoxia but it reduced PVR after subsequent acute exposure to hypoxia. Our findings in normoxia do not suggest a direct acute pulmonary vasodilator effect of acetazolamide. The reduction of PVR during hypoxia requires further corroboration. Whether acetazolamide improves PH when given over a prolonged period by stimulating ventilation, increasing oxygenation, and/or altering vascular inflammation and remodeling remains to be investigated.
Pflügers Archiv: European Journal of Physiology, Apr 8, 2006
Human HeLa cells transfected with mouse connexin45 were used to explore the experimental conditio... more Human HeLa cells transfected with mouse connexin45 were used to explore the experimental conditions suitable to measure currents carried by gap junction hemichannels. Experiments were performed with a voltageclamp technique and whole-cell recording. Lowering [Ca 2+ ] o from 2 mM to 20 nM evoked an extra current, I m , putatively carried by Cx45 hemichannels. However, the variability of I m (size, voltage sensitivity, kinetics) suggested the involvement of other channels. The finding that growth medium in the incubator increased the osmolarity with time implied that volume-regulated anion channels (VRAC) may participate. This assumption was reinforced by the following observations. On the one hand, keeping [Ca 2+ ] o normal while the osmolarity of the extracellular solution was reduced from 310 to 290 mOsm yielded a current characteristic of VRAC; I VRAC activated/deactivated at negative/positive voltage, giving rise to the conductance functions g VRAC,inst =f(V m) (inst: instantaneous; V m : membrane potential) and g VRAC,ss =f (V m) (ss: steady state). Moreover, it was reversibly inhibited by mibefradil, a Clchannel blocker (binding constant K d =38 μM, Hill coefficient n=12), but not by the gap junction channel blocker 18α-glycyrrhetinic acid. On the other hand, minimizing the osmotic imbalance while [Ca 2+ ] o was reduced led to a current typical for Cx45 hemichannels; I hc activated/deactivated at positive/negative voltage. Furthermore, it was reversibly inhibited by 18α-glycyrrhetinic acid or palmitoleic acid, but not by mibefradil. Computations based on g VRAC,ss =f(V m) and g hc,ss =f(V m) indicated that the concomitant operation of both currents results in a bell-shaped conductance-voltage relationship. The functional implications of the data presented are discussed. Conceivably, VRAC and hemichannels are involved in a common signaling pathway.
We tested whether long-term oxygen therapy (LTOT) at home would improve exercise capacity and qua... more We tested whether long-term oxygen therapy (LTOT) at home would improve exercise capacity and quality of life in exercise-desaturating patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension (PAH/CTEPH). In this randomized, sham-controlled, double-blind, cross-over trial PAH/CTEPH-patients with exercise desaturation (resting PaO2>7.3 kPa) were recruited. They received either LTOT or sham air for 5 weeks (2-3l/min via nasal cannula, during nights and daytime rest, 9-13h/day) according to a randomized cross-over design, with 2 weeks wash-out in between. Co-primary outcomes were the 6-minute walking distance (6MWD) and the SF-36 physical component summary score (PCS). 30 patients (14/16 PAH/CTEPH, age 60±15y, BMI 28±6kg/m2, 6MWD 484±117m, mPAP 39±11mmHg) pretreated with endothelin-receptor antagonists (60%) and/or phosphodiesterase-5-inhibitors (43%) were randomized. There was a significant treatment effect of oxygen on the 6MWD (figure), whereas the effect on the PCS was non-significant.
* Available only in 64 patients who had arterial blood gases at the end of the HAST. Predictive v... more * Available only in 64 patients who had arterial blood gases at the end of the HAST. Predictive variables revealing a p<0.05 in univariate analysis were tested with age, sex and BMI in the multivariate model as predefined.
The question addressed by the study: Chronic exposure to hypoxia increases pulmonary artery press... more The question addressed by the study: Chronic exposure to hypoxia increases pulmonary artery pressure (PAP) in highlanders, but the criteria for diagnosis of high-altitude pulmonary hypertension (HAPH) are debated. We assessed cardiac function and PAP in highlanders at 3250 m and explored HAPH prevalence using different definitions. Patients and methods: Central Asian highlanders free of overt cardiorespiratory disease, permanently living at 2500-3500 m compared to age-matched lowlanders living <800 m. Participants underwent echocardiography close to their altitude of residence (at 3250 m versus 760 m). Results: 173 participants (97 highlanders, 76 lowlanders), mean±SD age 49±9 years (49% females) completed the study. Results in lowlanders versus highlanders were systolic PAP (23±5 versus 30±10 mmHg), right ventricular fractional area change (42±6% versus 39±8%), tricuspid annular plane systolic excursion (2.1±0.3 versus 2.0±0.3 cm), right atrial volume index (20±6 versus 23±8 mL•m −2), left ventricular ejection fraction (62±4% versus 57±5%) and stroke volume (64±10 versus 57±11 mL); all between-group comparisons p<0.05. Depending on criteria, HAPH prevalence varied between 6% and 35%. The answer to the question: Chronic exposure to hypoxia in highlanders is associated with higher PAP and slight alterations in right and left heart function compared to lowlanders. The prevalence of HAPH in this large highlander cohort varies between 6% according to expert consensus definition of chronic high-altitude disease to 35% according to the most recent definition of pulmonary hypertension proposed for lowlanders. This study was registered at ClinicalTrials.gov as NCT03165656.
Purpose: To demonstrate the importance of collaboration between ophthalmologists and internists. ... more Purpose: To demonstrate the importance of collaboration between ophthalmologists and internists. Design: Cryoglobulinemia is a systemic vascularite. Ophthalmologic complications are rare and not well known. Purtscher-like retinopathy may occur in this context. Case report: We report the case of a patient who presented a severe visual loss in the course of a hepatitis C. The ophthalmic examination shows a both ischemic and hemorrhagic bilateral retinopathy called Purtscher-like retinopathy. Cryoglobulinemia complicating a hepatitis C was discovered in our patient. Conclusions: This case illustrates a cryoglobulinemia complicating by a Purtscher-like retinopathy. The diagnosis has been possible thanks to collaboration between ophthalmologists and internists. We propose a few hypotheses to explain retinopathy pathogeny.
Neuromodulatory control by oxytocin is essential to a wide range of social 1,2 , parental 3 and s... more Neuromodulatory control by oxytocin is essential to a wide range of social 1,2 , parental 3 and stress-related behaviors 4. Autism spectrum disorders (ASD) are associated with deficiencies in oxytocin levels 5 and with genetic alterations of the oxytocin receptor (OXTR) 6. Thirty years ago, Muhlethaler et al. 7 found that oxytocin increases the firing of inhibitory hippocampal neurons, but it remains unclear how elevated inhibition could account for the ability of oxytocin to improve information processing in the brain. Here, we describe a simple yet powerful mechanism by which oxytocin enhances cortical information transfer 8 while simultaneously lowering background activity, thus greatly improving signal-to-noise. Increased fast-spiking interneuron (FSI) activity not only suppresses spontaneous pyramidal cell firing, but also enhances the fidelity of spike transmission and sharpens spike timing. Use-dependent depression at the FSI-pyramidal cell synapse is both necessary and sufficient for the enhanced spike throughput. Notably, we show the generality of this novel circuit mechanism by activation of FSIs with cholecystokinin, or with channelrhodopsin-2. This provides insight into how a diffusely delivered neuromodulator can improve the performance of neural circuitry that requires synapse specificity and millisecond precision. Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Background: Asthma rehabilitation at high altitude is common. Little is known about the acute and... more Background: Asthma rehabilitation at high altitude is common. Little is known about the acute and subacute cardiopulmonary acclimatization to high altitude in middle-aged asthmatics without other comorbidities.Methods: In this prospective study in lowlander subjects with mostly mild asthma who revealed an asthma control questionnaire score &gt;0.75 and participated in a three-week rehabilitation program, we assessed systolic pulmonary artery pressure (sPAP), cardiac function, and extravascular lung water (EVLW) at 760 m (baseline) by Doppler-echocardiography and on the second (acute) and last day (subacute) at a high altitude clinic in Kyrgyzstan (3100 m).Results: The study included 22 patients (eight male) with a mean age of 44.3 ± 12.4 years, body mass index of 25.8 ± 4.7 kg/m2, a forced expiratory volume in 1 s of 92% ± 19% predicted (post-bronchodilator), and partially uncontrolled asthma. sPAP increased from 21.8 mmHg by mean difference by 7.5 [95% confidence interval 3.9 to 10.5] mmHg (p &lt; 0.001) during acute exposure and by 4.8 [1.0 to 8.6] mmHg (p = 0.014) during subacute exposure. The right-ventricular-to-pulmonary-artery coupling expressed by TAPSE/sPAP decreased from 1.1 by −0.2 [−0.3 to −0.1] mm/mmHg (p &lt; 0.001) during acute exposure and by −0.2 [−0.3 to −0.1] mm/mmHg (p = 0.002) during subacute exposure, accordingly. EVLW significantly increased from baseline (1.3 ± 1.8) to acute hypoxia (5.5 ± 3.5, p &lt; 0.001) but showed no difference after 3 weeks (2.0 ± 1.8).Conclusion: In otherwise healthy asthmatics, acute exposure to hypoxia at high altitude increases pulmonary artery pressure (PAP) and EVLW. During subacute exposure, PAP remains increased, but EVLW returns to baseline values, suggesting compensatory mechanisms that contribute to EVLW homeostasis during acclimatization.
Asthma rehabilitation at high vs. low altitude and its impact on exhaled nitric oxide and sensiti... more Asthma rehabilitation at high vs. low altitude and its impact on exhaled nitric oxide and sensitization patterns: Randomized parallel-group trial, Respiratory Medicine (2020), doi: https://doi.org/10.1016/ j.rmed.2020.106040. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Aim: High altitude (HA) hypoxia may affect cognitive performance and sleep quality. Further, vigi... more Aim: High altitude (HA) hypoxia may affect cognitive performance and sleep quality. Further, vigilance is reduced following sleep deprivation. We investigated the effect on vigilance, actigraphic sleep indices, and their relationships with acute mountain sickness (AMS) during very HA exposure, acclimatization, and re-exposure. Methods: A total of 21 healthy altitude-naive individuals (25 ± 4 years; 13 females) completed 2 cycles of altitude exposure separated by 7 days at low altitude (LA, 520 m). Participants slept at 2900 m and spent the day at HA, (5050 m). We report acute altitude exposure on Day 1 (LA vs. HA1) and after 6 days of acclimatization (HA1 vs. HA6). Vigilance was quantified by reaction speed in the 10-min psychomotor vigilance test reaction speed (PVT-RS). AMS was evaluated using the Environmental Symptoms Questionnaire Cerebral Score (AMS-C score). Nocturnal rest/activity was recorded to estimate sleep duration using actigraphy. Results: In Cycle 1, PVT-RS was slower at HA1 compared to LA (4.1 ± 0.8 vs. 4.5 ± 0.6 s −1 , respectively, p = 0.029), but not at HA6 (4.6 ± 0.7; p > 0.05). In Cycle 2, PVT-RS at HA1 (4.6 ± 0.7) and HA6 (4.8 ± 0.6) were not different from LA (4.8 ± 0.6, p > 0.05) and significantly greater than corresponding values in Cycle 1. In both cycles, AMS scores were higher at HA1 than at LA and HA6 (p < 0.05). Estimated sleep durations (TST) at LA, 1st and 5th nights were 431.3 ± 28.7, 418.1 ± 48.6, and 379.7 ± 51.4 min, respectively, in Cycle 1 and they were significantly reduced during acclimatization exposures (LA vs. 1st night, p > 0.05; LA vs. 5th night, p = 0.012; and 1st vs. 5th night, p = 0.054). LA, 1st and 5th nights TST in Cycle 2 were 477.5 ± 96.9, 430.9 ± 34, and 341.4 ± 32.2, respectively, and we observed similar deteriorations in TST as in Cycle 1 (LA vs. 1st night, p > 0.05; LA vs. 5th night, p = 0.001; and 1st vs. 5th night, p < 0.0001). At HA1, subjects who reported higher AMS-C scores exhibited slower PVT-RS (r = −0.56; p < 0.01). Subjects with higher AMS-C scores took longer time to react to the stimuli during acute exposure (r = 0.62, p < 0.01) during HA1 of Cycle 1.
TEN/DRESS overlap syndrome can be difficult to diagnose, especially if it is masked by comorbidit... more TEN/DRESS overlap syndrome can be difficult to diagnose, especially if it is masked by comorbidities in critically ill patients in intensive care units. The existing therapy for the two conditions is also a major challenge for the treating team. A possible alternative, especially for refractory cases, is benralizumab as an IL-5-receptor alpha-chain-specific humanized monoclonal antibody (IgG1k). We are able to show a successful treatment in this case report.
Enteral feed bezoars are difficult to treat and can lead to serious adverse events. There is no s... more Enteral feed bezoars are difficult to treat and can lead to serious adverse events. There is no standardized treatment approach and various strategies have been suggested. We herein describe three cases of successful dissolutions of feed bezoars consisting of Promote ® Fibre Plus with sodium bicarbonate 8.4% in critically ill patients. To provide the rationale for this approach, the effect of sodium bicarbonate 8.4% on enteral feed concretions was studied in vitro. First, Promote ® Fibres Plus was incubated with hydrochloric acid with gradually decreasing pH values to establish a pH at which the solution solidifies. The resulting enteral feed concretion was exposed to sodium bicarbonate 8.4% and Coca Cola ®. All patients were successfully treated with sodium bicarbonate 8.4% without the need of lengthy or repeat endoscopies. In vitro, Promote ® Fibres Plus solidifies when acidified below a pH of 4.6. The resulting enteral feed concretions dissolved when exposed to sodium bicarbonate 8.4%. Incubation with Coca Cola ® had no effect. We provide evidence that enteral feed bezoars consisting of Promote ® Fibres Plus can be efficiently and safely treated with sodium bicarbonate 8.4% offering a new approach for daily patient care.
The aim of the study was to investigate the pulmonary haemodynamic response to exercise in Centra... more The aim of the study was to investigate the pulmonary haemodynamic response to exercise in Central Asian high-and lowlanders. This was a cross-sectional study in Central Asian highlanders (living >2500 m) compared with lowlanders (living <800 m), assessing cardiac function, including tricuspid regurgitation pressure gradient (TRPG), cardiac index and tricuspid annular plane systolic excursion (TAPSE) by echocardiography combined with heart rate and oxygen saturation measured by pulse oximetry (S pO 2) during submaximal stepwise cycle exercise (10 W increase per 3 min) at their altitude of residence (at 760 m or 3250 m, respectively). 52 highlanders (26 females; aged 47.9±10.7 years; body mass index (BMI) 26.7±4.6 kg•m −2 ; heart rate 75±11 beats•min −1 ; S pO 2 91±5%;) and 22 lowlanders (eight females; age 42.3±8.0 years; BMI 26.9±4.1 kg•m −2 ; heart rate 68±7 beats•min −1 ; S pO 2 96±1%) were studied. Highlanders had a lower resting S pO 2 compared to lowlanders but change during exercise was similar between groups (highlanders versus lowlanders −1.4±2.9% versus −0.4±1.1%, respectively, p=0.133). Highlanders had a significantly elevated TRPG and exercise-induced increase was significantly higher (13.6±10.5 mmHg versus 6.1±4.8 mmHg, difference 7.5 (2.8 to 12.2) mmHg; p=0.002), whereas cardiac index increase was slightly lower in highlanders (2.02±0.89 L•min −1 versus 1.78±0.61 L•min −1 , difference 0.24 (−0.13 to 0.61) L•min −1 ; p=0.206) resulting in a significantly steeper pressure-flow ratio (ΔTRPG/Δcardiac index) in highlanders 9.4±11.4 WU and lowlanders 3.0±2.4 WU (difference 6.4 (1.4 to 11.3) WU; p=0.012). Right ventriculararterial coupling (TAPSE/TRPG) was significantly lower in highlanders but no significant difference in change with exercise in between groups was detected (−0.01 (−0.20 to 0.18); p=0.901). In highlanders, chronic exposure to hypoxia leads to higher pulmonary artery pressure and a steeper pressure-flow relation during exercise. @ERSpublications Central Asian highlanders living between 2500 and 3600 m assessed by stress echocardiography showed that chronic exposure to hypoxia leads to a steeper pressure-flow curve during exercise and worse right ventricular-arterial coupling compared to lowlanders https://bit.ly/3qlvhOj
Introduction: Patients with precapillary pulmonary hypertension (PH, pulmonary arterial or chroni... more Introduction: Patients with precapillary pulmonary hypertension (PH, pulmonary arterial or chronic thromboembolic pulmonary hypertension, PAH/CTEPH) may experience disease deterioration upon exposure to a hypoxic environment during air travel or altitude sojourns due to hypoxic pulmonary vasoconstriction. We investigated the effect of breathing a hypoxic air mixture on pulmonary hemodynamics and blood gases in PH in comparison with unaffected controls. Methods: Patients scheduled for diagnostic right heart catheterization had hemodynamic assessments under ambient air (FiO 2 0.21) and after 10 min of breathing nitrogen-enriched air (hypoxia FiO 2 0.16). Patients were stratified according to their mean pulmonary arterial pressure (mPAP): PH (mPAP $25mmHg, pulmonary artery wedge pressure (PAWP) #15mmHg), unaffected controls (patients undergoing RHC for evaluation of dyspnea with mPAP< 20mmHg) and intermediate (mPAP 20-24mmHg). Results: 20 patients with PH (12 females, 8 PAH, 12 CTEPH; meanAESD age 63AE14y), 12 controls (12 females, age 63AE7y) and 7 patients from the intermediate group (3 females, age 66AE12y) were included. PaO 2 significantly decreased in all groups upon exposure to hypoxia (see table). However, hypoxemia was not accompanied by significant changes in mPAP or cardiac index in any group. Unexpectedly, pulmonary vascular resistance significantly increased in the control group. The test was well tolerated by all participants. Conclusions: Our data suggest that a short-term exposure to a moderately reduced FiO 2 in patients with PAH/CTEPH associated with chronic hypoxemia in sea level conditions seems not to further exacerbate derangements in pulmonary hemodynamics. Whether the hemodynamic effects of a short hypoxic challenge are in concordance with the response to prolonged hypoxia remains to be determined.
Introduction: Lifelong exposure to hypobaric hypoxia induces physiologic adaptations in highlande... more Introduction: Lifelong exposure to hypobaric hypoxia induces physiologic adaptations in highlanders that may modify exercise performance; however, reference data for altitude populations are scant. Methods: Lifelong residents of the Tien Shan mountain range, 2,500-3,500 m, Kyrgyzstan, free of cardiopulmonary disease, underwent cardiopulmonary cycle exercise tests with a progressive ramp protocol to exhaustion at 3,250 m. ECG, breath-by-breath pulmonary gas exchange, and oxygen saturation by pulse oximetry (SpO2) were measured. Results: Among 81 highlanders, age (mean ± SD) 48 ± 10 years, 46% women, SpO2 at rest was 88% ± 2%, peak oxygen uptake (V'O2peak) was 21.6 ± 5.9 mL/kg/min (76% ± 15% predicted for a low-altitude reference population); peak work rate (Wpeak) was 117 ± 37 W (77% ± 17% predicted), SpO2 at peak was 84% ± 5%, heart rate reserve (220-age-maximal heart rate) was 28 ± 17/min, ventilatory reserve (maximal voluntary ventilation-maximal minute ventilation) was 68 ± 32 l/min, and respiratory exchange ratio was 1.03 ± 0.09. Peak BORG-CR10 dyspnea and leg fatigue scores were 5.1 ± 2.0 and 6.3 ± 2.1. In multivariable linear regression analyses, age and sex were robust determinants of Wpeak, V'O2peak, and metabolic equivalent (MET) at peak, whereas body mass index, resting systolic blood pressure, and mean pulmonary artery pressure were not. Conclusions: The current study shows that V'O2peak and Wpeak of highlanders studied at 3,250 m, near their altitude of residence, were reduced by about one quarter compared with mean predicted values for lowlanders. The provided prediction models for V'O2peak, Wpeak, and METs in central Asian highlanders might be valuable for comparisons with other high altitude populations.
Aims: To test the acute hemodynamic effect of acetazolamide in patients with pulmonary hypertensi... more Aims: To test the acute hemodynamic effect of acetazolamide in patients with pulmonary hypertension (PH) under ambient air and hypoxia. Methods: Patients with pulmonary arterial or chronic thromboembolic PH (PAH/CTEPH) undergoing right heart catheterization were included in this randomized, placebo-controlled, double-blinded, crossover trial. The main outcome, pulmonary vascular resistance (PVR), further hemodynamics, blood-and cerebral oxygenation were measured 1 h after intravenous administration of 500 mg acetazolamide or placebo-saline on ambient air (normoxia) and at the end of breathing hypoxic gas (F I O 2 0.15, hypoxia) for 15 min. Results: 24 PH-patients, 71% men, mean ± SD age 59 ± 14 years, BMI 28 ± 5 kg/m 2 , PVR 4.7 ± 2.1 WU participated. Mean PVR after acetazolamide vs. placebo was 5.5 ± 3.0 vs. 5.3 ± 3.0 WU; mean difference (95% CI) 0.2 (−0.2-0.6, p = 0.341). Heart rate was higher after acetazolamide (79 ± 12 vs. 77 ± 11 bpm, p = 0.026), pH was lower (7.40 ± 0.02 vs. 7.42 ± 0.03, p = 0.002) but PaCO 2 and PaO 2 remained unchanged while cerebral tissue oxygenation increased (71 ± 6 vs. 69 ± 6%, p = 0.017). In acute hypoxia, acetazolamide decreased PVR by 0.4 WU (0.0-0.9, p = 0.046) while PaO 2 and PaCO 2 were not changed. No adverse effects occurred. Conclusions: In patients with PAH/CTEPH, i.v. acetazolamide did not change pulmonary hemodynamics compared to placebo after 1 hour in normoxia but it reduced PVR after subsequent acute exposure to hypoxia. Our findings in normoxia do not suggest a direct acute pulmonary vasodilator effect of acetazolamide. The reduction of PVR during hypoxia requires further corroboration. Whether acetazolamide improves PH when given over a prolonged period by stimulating ventilation, increasing oxygenation, and/or altering vascular inflammation and remodeling remains to be investigated.
Pflügers Archiv: European Journal of Physiology, Apr 8, 2006
Human HeLa cells transfected with mouse connexin45 were used to explore the experimental conditio... more Human HeLa cells transfected with mouse connexin45 were used to explore the experimental conditions suitable to measure currents carried by gap junction hemichannels. Experiments were performed with a voltageclamp technique and whole-cell recording. Lowering [Ca 2+ ] o from 2 mM to 20 nM evoked an extra current, I m , putatively carried by Cx45 hemichannels. However, the variability of I m (size, voltage sensitivity, kinetics) suggested the involvement of other channels. The finding that growth medium in the incubator increased the osmolarity with time implied that volume-regulated anion channels (VRAC) may participate. This assumption was reinforced by the following observations. On the one hand, keeping [Ca 2+ ] o normal while the osmolarity of the extracellular solution was reduced from 310 to 290 mOsm yielded a current characteristic of VRAC; I VRAC activated/deactivated at negative/positive voltage, giving rise to the conductance functions g VRAC,inst =f(V m) (inst: instantaneous; V m : membrane potential) and g VRAC,ss =f (V m) (ss: steady state). Moreover, it was reversibly inhibited by mibefradil, a Clchannel blocker (binding constant K d =38 μM, Hill coefficient n=12), but not by the gap junction channel blocker 18α-glycyrrhetinic acid. On the other hand, minimizing the osmotic imbalance while [Ca 2+ ] o was reduced led to a current typical for Cx45 hemichannels; I hc activated/deactivated at positive/negative voltage. Furthermore, it was reversibly inhibited by 18α-glycyrrhetinic acid or palmitoleic acid, but not by mibefradil. Computations based on g VRAC,ss =f(V m) and g hc,ss =f(V m) indicated that the concomitant operation of both currents results in a bell-shaped conductance-voltage relationship. The functional implications of the data presented are discussed. Conceivably, VRAC and hemichannels are involved in a common signaling pathway.
We tested whether long-term oxygen therapy (LTOT) at home would improve exercise capacity and qua... more We tested whether long-term oxygen therapy (LTOT) at home would improve exercise capacity and quality of life in exercise-desaturating patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension (PAH/CTEPH). In this randomized, sham-controlled, double-blind, cross-over trial PAH/CTEPH-patients with exercise desaturation (resting PaO2>7.3 kPa) were recruited. They received either LTOT or sham air for 5 weeks (2-3l/min via nasal cannula, during nights and daytime rest, 9-13h/day) according to a randomized cross-over design, with 2 weeks wash-out in between. Co-primary outcomes were the 6-minute walking distance (6MWD) and the SF-36 physical component summary score (PCS). 30 patients (14/16 PAH/CTEPH, age 60±15y, BMI 28±6kg/m2, 6MWD 484±117m, mPAP 39±11mmHg) pretreated with endothelin-receptor antagonists (60%) and/or phosphodiesterase-5-inhibitors (43%) were randomized. There was a significant treatment effect of oxygen on the 6MWD (figure), whereas the effect on the PCS was non-significant.
* Available only in 64 patients who had arterial blood gases at the end of the HAST. Predictive v... more * Available only in 64 patients who had arterial blood gases at the end of the HAST. Predictive variables revealing a p<0.05 in univariate analysis were tested with age, sex and BMI in the multivariate model as predefined.
The question addressed by the study: Chronic exposure to hypoxia increases pulmonary artery press... more The question addressed by the study: Chronic exposure to hypoxia increases pulmonary artery pressure (PAP) in highlanders, but the criteria for diagnosis of high-altitude pulmonary hypertension (HAPH) are debated. We assessed cardiac function and PAP in highlanders at 3250 m and explored HAPH prevalence using different definitions. Patients and methods: Central Asian highlanders free of overt cardiorespiratory disease, permanently living at 2500-3500 m compared to age-matched lowlanders living <800 m. Participants underwent echocardiography close to their altitude of residence (at 3250 m versus 760 m). Results: 173 participants (97 highlanders, 76 lowlanders), mean±SD age 49±9 years (49% females) completed the study. Results in lowlanders versus highlanders were systolic PAP (23±5 versus 30±10 mmHg), right ventricular fractional area change (42±6% versus 39±8%), tricuspid annular plane systolic excursion (2.1±0.3 versus 2.0±0.3 cm), right atrial volume index (20±6 versus 23±8 mL•m −2), left ventricular ejection fraction (62±4% versus 57±5%) and stroke volume (64±10 versus 57±11 mL); all between-group comparisons p<0.05. Depending on criteria, HAPH prevalence varied between 6% and 35%. The answer to the question: Chronic exposure to hypoxia in highlanders is associated with higher PAP and slight alterations in right and left heart function compared to lowlanders. The prevalence of HAPH in this large highlander cohort varies between 6% according to expert consensus definition of chronic high-altitude disease to 35% according to the most recent definition of pulmonary hypertension proposed for lowlanders. This study was registered at ClinicalTrials.gov as NCT03165656.
Purpose: To demonstrate the importance of collaboration between ophthalmologists and internists. ... more Purpose: To demonstrate the importance of collaboration between ophthalmologists and internists. Design: Cryoglobulinemia is a systemic vascularite. Ophthalmologic complications are rare and not well known. Purtscher-like retinopathy may occur in this context. Case report: We report the case of a patient who presented a severe visual loss in the course of a hepatitis C. The ophthalmic examination shows a both ischemic and hemorrhagic bilateral retinopathy called Purtscher-like retinopathy. Cryoglobulinemia complicating a hepatitis C was discovered in our patient. Conclusions: This case illustrates a cryoglobulinemia complicating by a Purtscher-like retinopathy. The diagnosis has been possible thanks to collaboration between ophthalmologists and internists. We propose a few hypotheses to explain retinopathy pathogeny.
Neuromodulatory control by oxytocin is essential to a wide range of social 1,2 , parental 3 and s... more Neuromodulatory control by oxytocin is essential to a wide range of social 1,2 , parental 3 and stress-related behaviors 4. Autism spectrum disorders (ASD) are associated with deficiencies in oxytocin levels 5 and with genetic alterations of the oxytocin receptor (OXTR) 6. Thirty years ago, Muhlethaler et al. 7 found that oxytocin increases the firing of inhibitory hippocampal neurons, but it remains unclear how elevated inhibition could account for the ability of oxytocin to improve information processing in the brain. Here, we describe a simple yet powerful mechanism by which oxytocin enhances cortical information transfer 8 while simultaneously lowering background activity, thus greatly improving signal-to-noise. Increased fast-spiking interneuron (FSI) activity not only suppresses spontaneous pyramidal cell firing, but also enhances the fidelity of spike transmission and sharpens spike timing. Use-dependent depression at the FSI-pyramidal cell synapse is both necessary and sufficient for the enhanced spike throughput. Notably, we show the generality of this novel circuit mechanism by activation of FSIs with cholecystokinin, or with channelrhodopsin-2. This provides insight into how a diffusely delivered neuromodulator can improve the performance of neural circuitry that requires synapse specificity and millisecond precision. Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Background: Asthma rehabilitation at high altitude is common. Little is known about the acute and... more Background: Asthma rehabilitation at high altitude is common. Little is known about the acute and subacute cardiopulmonary acclimatization to high altitude in middle-aged asthmatics without other comorbidities.Methods: In this prospective study in lowlander subjects with mostly mild asthma who revealed an asthma control questionnaire score &gt;0.75 and participated in a three-week rehabilitation program, we assessed systolic pulmonary artery pressure (sPAP), cardiac function, and extravascular lung water (EVLW) at 760 m (baseline) by Doppler-echocardiography and on the second (acute) and last day (subacute) at a high altitude clinic in Kyrgyzstan (3100 m).Results: The study included 22 patients (eight male) with a mean age of 44.3 ± 12.4 years, body mass index of 25.8 ± 4.7 kg/m2, a forced expiratory volume in 1 s of 92% ± 19% predicted (post-bronchodilator), and partially uncontrolled asthma. sPAP increased from 21.8 mmHg by mean difference by 7.5 [95% confidence interval 3.9 to 10.5] mmHg (p &lt; 0.001) during acute exposure and by 4.8 [1.0 to 8.6] mmHg (p = 0.014) during subacute exposure. The right-ventricular-to-pulmonary-artery coupling expressed by TAPSE/sPAP decreased from 1.1 by −0.2 [−0.3 to −0.1] mm/mmHg (p &lt; 0.001) during acute exposure and by −0.2 [−0.3 to −0.1] mm/mmHg (p = 0.002) during subacute exposure, accordingly. EVLW significantly increased from baseline (1.3 ± 1.8) to acute hypoxia (5.5 ± 3.5, p &lt; 0.001) but showed no difference after 3 weeks (2.0 ± 1.8).Conclusion: In otherwise healthy asthmatics, acute exposure to hypoxia at high altitude increases pulmonary artery pressure (PAP) and EVLW. During subacute exposure, PAP remains increased, but EVLW returns to baseline values, suggesting compensatory mechanisms that contribute to EVLW homeostasis during acclimatization.
Asthma rehabilitation at high vs. low altitude and its impact on exhaled nitric oxide and sensiti... more Asthma rehabilitation at high vs. low altitude and its impact on exhaled nitric oxide and sensitization patterns: Randomized parallel-group trial, Respiratory Medicine (2020), doi: https://doi.org/10.1016/ j.rmed.2020.106040. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Aim: High altitude (HA) hypoxia may affect cognitive performance and sleep quality. Further, vigi... more Aim: High altitude (HA) hypoxia may affect cognitive performance and sleep quality. Further, vigilance is reduced following sleep deprivation. We investigated the effect on vigilance, actigraphic sleep indices, and their relationships with acute mountain sickness (AMS) during very HA exposure, acclimatization, and re-exposure. Methods: A total of 21 healthy altitude-naive individuals (25 ± 4 years; 13 females) completed 2 cycles of altitude exposure separated by 7 days at low altitude (LA, 520 m). Participants slept at 2900 m and spent the day at HA, (5050 m). We report acute altitude exposure on Day 1 (LA vs. HA1) and after 6 days of acclimatization (HA1 vs. HA6). Vigilance was quantified by reaction speed in the 10-min psychomotor vigilance test reaction speed (PVT-RS). AMS was evaluated using the Environmental Symptoms Questionnaire Cerebral Score (AMS-C score). Nocturnal rest/activity was recorded to estimate sleep duration using actigraphy. Results: In Cycle 1, PVT-RS was slower at HA1 compared to LA (4.1 ± 0.8 vs. 4.5 ± 0.6 s −1 , respectively, p = 0.029), but not at HA6 (4.6 ± 0.7; p > 0.05). In Cycle 2, PVT-RS at HA1 (4.6 ± 0.7) and HA6 (4.8 ± 0.6) were not different from LA (4.8 ± 0.6, p > 0.05) and significantly greater than corresponding values in Cycle 1. In both cycles, AMS scores were higher at HA1 than at LA and HA6 (p < 0.05). Estimated sleep durations (TST) at LA, 1st and 5th nights were 431.3 ± 28.7, 418.1 ± 48.6, and 379.7 ± 51.4 min, respectively, in Cycle 1 and they were significantly reduced during acclimatization exposures (LA vs. 1st night, p > 0.05; LA vs. 5th night, p = 0.012; and 1st vs. 5th night, p = 0.054). LA, 1st and 5th nights TST in Cycle 2 were 477.5 ± 96.9, 430.9 ± 34, and 341.4 ± 32.2, respectively, and we observed similar deteriorations in TST as in Cycle 1 (LA vs. 1st night, p > 0.05; LA vs. 5th night, p = 0.001; and 1st vs. 5th night, p < 0.0001). At HA1, subjects who reported higher AMS-C scores exhibited slower PVT-RS (r = −0.56; p < 0.01). Subjects with higher AMS-C scores took longer time to react to the stimuli during acute exposure (r = 0.62, p < 0.01) during HA1 of Cycle 1.
TEN/DRESS overlap syndrome can be difficult to diagnose, especially if it is masked by comorbidit... more TEN/DRESS overlap syndrome can be difficult to diagnose, especially if it is masked by comorbidities in critically ill patients in intensive care units. The existing therapy for the two conditions is also a major challenge for the treating team. A possible alternative, especially for refractory cases, is benralizumab as an IL-5-receptor alpha-chain-specific humanized monoclonal antibody (IgG1k). We are able to show a successful treatment in this case report.
Enteral feed bezoars are difficult to treat and can lead to serious adverse events. There is no s... more Enteral feed bezoars are difficult to treat and can lead to serious adverse events. There is no standardized treatment approach and various strategies have been suggested. We herein describe three cases of successful dissolutions of feed bezoars consisting of Promote ® Fibre Plus with sodium bicarbonate 8.4% in critically ill patients. To provide the rationale for this approach, the effect of sodium bicarbonate 8.4% on enteral feed concretions was studied in vitro. First, Promote ® Fibres Plus was incubated with hydrochloric acid with gradually decreasing pH values to establish a pH at which the solution solidifies. The resulting enteral feed concretion was exposed to sodium bicarbonate 8.4% and Coca Cola ®. All patients were successfully treated with sodium bicarbonate 8.4% without the need of lengthy or repeat endoscopies. In vitro, Promote ® Fibres Plus solidifies when acidified below a pH of 4.6. The resulting enteral feed concretions dissolved when exposed to sodium bicarbonate 8.4%. Incubation with Coca Cola ® had no effect. We provide evidence that enteral feed bezoars consisting of Promote ® Fibres Plus can be efficiently and safely treated with sodium bicarbonate 8.4% offering a new approach for daily patient care.
The aim of the study was to investigate the pulmonary haemodynamic response to exercise in Centra... more The aim of the study was to investigate the pulmonary haemodynamic response to exercise in Central Asian high-and lowlanders. This was a cross-sectional study in Central Asian highlanders (living >2500 m) compared with lowlanders (living <800 m), assessing cardiac function, including tricuspid regurgitation pressure gradient (TRPG), cardiac index and tricuspid annular plane systolic excursion (TAPSE) by echocardiography combined with heart rate and oxygen saturation measured by pulse oximetry (S pO 2) during submaximal stepwise cycle exercise (10 W increase per 3 min) at their altitude of residence (at 760 m or 3250 m, respectively). 52 highlanders (26 females; aged 47.9±10.7 years; body mass index (BMI) 26.7±4.6 kg•m −2 ; heart rate 75±11 beats•min −1 ; S pO 2 91±5%;) and 22 lowlanders (eight females; age 42.3±8.0 years; BMI 26.9±4.1 kg•m −2 ; heart rate 68±7 beats•min −1 ; S pO 2 96±1%) were studied. Highlanders had a lower resting S pO 2 compared to lowlanders but change during exercise was similar between groups (highlanders versus lowlanders −1.4±2.9% versus −0.4±1.1%, respectively, p=0.133). Highlanders had a significantly elevated TRPG and exercise-induced increase was significantly higher (13.6±10.5 mmHg versus 6.1±4.8 mmHg, difference 7.5 (2.8 to 12.2) mmHg; p=0.002), whereas cardiac index increase was slightly lower in highlanders (2.02±0.89 L•min −1 versus 1.78±0.61 L•min −1 , difference 0.24 (−0.13 to 0.61) L•min −1 ; p=0.206) resulting in a significantly steeper pressure-flow ratio (ΔTRPG/Δcardiac index) in highlanders 9.4±11.4 WU and lowlanders 3.0±2.4 WU (difference 6.4 (1.4 to 11.3) WU; p=0.012). Right ventriculararterial coupling (TAPSE/TRPG) was significantly lower in highlanders but no significant difference in change with exercise in between groups was detected (−0.01 (−0.20 to 0.18); p=0.901). In highlanders, chronic exposure to hypoxia leads to higher pulmonary artery pressure and a steeper pressure-flow relation during exercise. @ERSpublications Central Asian highlanders living between 2500 and 3600 m assessed by stress echocardiography showed that chronic exposure to hypoxia leads to a steeper pressure-flow curve during exercise and worse right ventricular-arterial coupling compared to lowlanders https://bit.ly/3qlvhOj
Introduction: Patients with precapillary pulmonary hypertension (PH, pulmonary arterial or chroni... more Introduction: Patients with precapillary pulmonary hypertension (PH, pulmonary arterial or chronic thromboembolic pulmonary hypertension, PAH/CTEPH) may experience disease deterioration upon exposure to a hypoxic environment during air travel or altitude sojourns due to hypoxic pulmonary vasoconstriction. We investigated the effect of breathing a hypoxic air mixture on pulmonary hemodynamics and blood gases in PH in comparison with unaffected controls. Methods: Patients scheduled for diagnostic right heart catheterization had hemodynamic assessments under ambient air (FiO 2 0.21) and after 10 min of breathing nitrogen-enriched air (hypoxia FiO 2 0.16). Patients were stratified according to their mean pulmonary arterial pressure (mPAP): PH (mPAP $25mmHg, pulmonary artery wedge pressure (PAWP) #15mmHg), unaffected controls (patients undergoing RHC for evaluation of dyspnea with mPAP< 20mmHg) and intermediate (mPAP 20-24mmHg). Results: 20 patients with PH (12 females, 8 PAH, 12 CTEPH; meanAESD age 63AE14y), 12 controls (12 females, age 63AE7y) and 7 patients from the intermediate group (3 females, age 66AE12y) were included. PaO 2 significantly decreased in all groups upon exposure to hypoxia (see table). However, hypoxemia was not accompanied by significant changes in mPAP or cardiac index in any group. Unexpectedly, pulmonary vascular resistance significantly increased in the control group. The test was well tolerated by all participants. Conclusions: Our data suggest that a short-term exposure to a moderately reduced FiO 2 in patients with PAH/CTEPH associated with chronic hypoxemia in sea level conditions seems not to further exacerbate derangements in pulmonary hemodynamics. Whether the hemodynamic effects of a short hypoxic challenge are in concordance with the response to prolonged hypoxia remains to be determined.
Introduction: Lifelong exposure to hypobaric hypoxia induces physiologic adaptations in highlande... more Introduction: Lifelong exposure to hypobaric hypoxia induces physiologic adaptations in highlanders that may modify exercise performance; however, reference data for altitude populations are scant. Methods: Lifelong residents of the Tien Shan mountain range, 2,500-3,500 m, Kyrgyzstan, free of cardiopulmonary disease, underwent cardiopulmonary cycle exercise tests with a progressive ramp protocol to exhaustion at 3,250 m. ECG, breath-by-breath pulmonary gas exchange, and oxygen saturation by pulse oximetry (SpO2) were measured. Results: Among 81 highlanders, age (mean ± SD) 48 ± 10 years, 46% women, SpO2 at rest was 88% ± 2%, peak oxygen uptake (V'O2peak) was 21.6 ± 5.9 mL/kg/min (76% ± 15% predicted for a low-altitude reference population); peak work rate (Wpeak) was 117 ± 37 W (77% ± 17% predicted), SpO2 at peak was 84% ± 5%, heart rate reserve (220-age-maximal heart rate) was 28 ± 17/min, ventilatory reserve (maximal voluntary ventilation-maximal minute ventilation) was 68 ± 32 l/min, and respiratory exchange ratio was 1.03 ± 0.09. Peak BORG-CR10 dyspnea and leg fatigue scores were 5.1 ± 2.0 and 6.3 ± 2.1. In multivariable linear regression analyses, age and sex were robust determinants of Wpeak, V'O2peak, and metabolic equivalent (MET) at peak, whereas body mass index, resting systolic blood pressure, and mean pulmonary artery pressure were not. Conclusions: The current study shows that V'O2peak and Wpeak of highlanders studied at 3,250 m, near their altitude of residence, were reduced by about one quarter compared with mean predicted values for lowlanders. The provided prediction models for V'O2peak, Wpeak, and METs in central Asian highlanders might be valuable for comparisons with other high altitude populations.
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