Outcome of acute respiratory distress syndrome in university and non-university hospitals in Germany.

BACKGROUND: This study investigates differences in treatment and outcome of ventilated patients with acute respiratory distress syndrome (ARDS) between university and non-university hospitals in Germany. METHODS: This subanalysis of a prospective, observational cohort study was performed to identify independent risk factors for mortality by examining: baseline factors, ventilator settings (e.g., driving pressure), complications, and care settings-for example, case volume of ventilated patients, size/type of intensive care unit (ICU), and type of hospital (university/non-university hospital). To control for potentially confounding factors at ARDS onset and to verify differences in mortality, ARDS patients in university vs non-university hospitals were compared using additional multivariable analysis. RESULTS: Of the 7540 patients admitted to 95 ICUs from 18 university and 62 non-university hospitals in May 2004, 1028 received mechanical ventilation and 198 developed ARDS. Although the characteristics of ARDS patients were very similar, hospital mortality was considerably lower in university compared with non-university hospitals (39.3% vs 57.5%; p = 0.012). Treatment in non-university hospitals was independently associated with increased mortality (OR (95% CI): 2.89 (1.31-6.38); p = 0.008). This was confirmed by additional independent comparisons between the two patient groups when controlling for confounding factors at ARDS onset. Higher driving pressures (OR 1.10; 1 cmH2O increments) were also independently associated with higher mortality. Compared with non-university hospitals, higher positive end-expiratory pressure (PEEP) (mean ± SD: 11.7 ± 4.7 vs 9.7 ± 3.7 cmH2O; p = 0.005) and lower driving pressures (15.1 ± 4.4 vs 17.0 ± 5.0 cmH2O; p = 0.02) were applied during therapeutic ventilation in university hospitals, and ventilation lasted twice as long (median (IQR): 16 (9-29) vs 8 (3-16) days; p < 0.001). CONCLUSIONS: Mortality risk of ARDS patients was considerably higher in non-university compared with university hospitals. Differences in ventilatory care between hospitals might explain this finding and may at least partially imply regionalization of care and the export of ventilatory strategies to non-university hospitals.

Combatting pain after orthopedic/trauma surgery- perioperative oral extended-release tapentadol vs. extended-release oxycodone/naloxone.

BACKGROUND: High post-operative pain scores after "minor" orthopedic/trauma surgery are in part attributed to inadequate prescription of opioid analgesics. Novel concepts aiming to achieve sufficient analgesia while minimizing opioid-related side effects by avoiding fluctuating plasma levels are based on perioperative oral administration of extended-release opioids beginning with the first dose pre-operatively. This is the first study to evaluate analgesic efficacy and side effect rates of extended-release tapentadol compared to oxycodone/naloxone following orthopedic/trauma surgery. METHODS: This randomized, observer-blinded, active-controlled prospective clinical trial had 2 co-primary endpoints: (1) Analgesic efficacy: Mean pain level on a numeric rating scale (NRS) from 0 to 10 during exercise over 5 days. (2) Safety: Side effect sum score of the following events: Nausea, vomiting, constipation, sedation, vertigo, somnolence. The study was powered to detect superiority of tapentadol for at least one endpoint pending statistical proof of non-inferiority for both endpoints in a first step. RESULTS: Two hundred sixty-six trauma patients were randomized to receive either tapentadol (n = 133) or oxycodone/naloxone (n = 133). Analgesic efficacy: Mean (±SD) daily pain levels in the first five post-operative days were 2.8 ± 1.3 in both groups. Mean maximum pain intensity during exercise in the first 24 h after surgery was 3.8 ± 1.9 (tapentadol) and 3.8 ± 2.1 (oxycodone/naloxone). Statistically tapentadol was non-inferior but not superior to oxycodone/naloxone. SAFETY: Vomiting on day 1 occurred in 11%, constipation in 35% of the tapentadol patients and in 16% and 30% of the oxycodone/naloxone patients (p = 0.60 and 0.33), respectively. The incidence of sedation/ vertigo was <10%, that of somnolence <2% in both groups (p > 0.3, respectively). The sum score of side effect events was 51% in the tapentadol vs. 49% in the oxycodone/naloxone group; risk difference 3% [95% CI, -8 to 14%]; p = 0.6). Non-inferiority of tapentadol could not be concluded as the pre-defined non-inferiority margin was exceeded. CONCLUSIONS: With both concepts, mean maximum pain intensity during exercise within the first 24 h after orthopedic/trauma surgery was reduced to a score of <4. This analgesic efficacy came at the cost of mainly gastro-intestinal side effects. Thus, we now use a prophylaxis against nausea and vomiting and pre-emptive laxatives as part of these concepts. TRIAL REGISTRATION: https://eudract.ema.europa.eu (EudraCT- Nr. 2011-003238-15 ); October 24th, 2012.

Anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis show distinct patterns of brain glucose metabolism in 18F-fluoro-2-deoxy-d-glucose positron emission tomography.

BACKGROUND: Pathogenic autoantibodies targeting the recently identified leucine rich glioma inactivated 1 protein and the subunit 1 of the N-methyl-D-aspartate receptor induce autoimmune encephalitis. A comparison of brain metabolic patterns in 18F-fluoro-2-deoxy-d-glucose positron emission tomography of anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis patients has not been performed yet and shall be helpful in differentiating these two most common forms of autoimmune encephalitis. METHODS: The brain 18F-fluoro-2-deoxy-d-glucose uptake from whole-body positron emission tomography of six anti-N-methyl-D-aspartate receptor encephalitis patients and four patients with anti-leucine rich glioma inactivated 1 protein encephalitis admitted to Hannover Medical School between 2008 and 2012 was retrospectively analyzed and compared to matched controls. RESULTS: Group analysis of anti-N-methyl-D-aspartate encephalitis patients demonstrated regionally limited hypermetabolism in frontotemporal areas contrasting an extensive hypometabolism in parietal lobes, whereas the anti-leucine rich glioma inactivated 1 protein syndrome was characterized by hypermetabolism in cerebellar, basal ganglia, occipital and precentral areas and minor frontomesial hypometabolism. CONCLUSIONS: This retrospective 18F-fluoro-2-deoxy-d-glucose positron emission tomography study provides novel evidence for distinct brain metabolic patterns in patients with anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis.

Inhibition of voltage-gated Na⁺ channels by the synthetic cannabinoid ajulemic acid.

BACKGROUND: The synthetic cannabinoid ajulemic acid has been demonstrated to alleviate pain in patients suffering from chronic neuropathic pain. Cannabinoids interact with several molecules within the pain circuit, including a potent inhibition of voltage-gated sodium channels. In this study, we closely characterized this property on neuronal and nonneuronal sodium channels. METHODS: The inhibition of sodium inward currents by ajulemic acid was studied in vitro. Human embryonic kidney 293t cells were used as the expression system for Nav1.2, 1.3, 1.4, 1.5, 1.5N406K, 1.5F1760A, and 1.7; Nav1.8 was transiently expressed in ND7/23 cells. Nav1.2, Nav1.3, and Nav 1.8 were from rats, and Nav1.4, Nav1.5, and Nav1.7 were of human origin. Sodium currents were analyzed by means of the whole cell patch-clamp technique. The investigated concentrations of ajulemic acid were 0.1, 0.3, 1, 3, 10, and 30 µmol/L. RESULTS: Ajulemic acid reversibly and concentration-dependently inhibited all voltage-gated sodium channel (Nav) isoforms investigated in this study, including Nav1.2, 1.3, 1.4, 1.5, 1.7, and 1.8. Tonic block of resting channels yielded half-maximal inhibitory concentration values between 2 and 9 µmol/L and was strongly enhanced on inactivated channels, suggesting state-dependent inhibition by ajulemic acid. Tonic block did not differ significantly when comparing Nav1.2 and Nav1.3, Nav1.4 and Nav1.5, and Nav1.7 and Nav1.8. Statistical analysis of other combinations of subunits (e.g., Nav1.2 and Nav1.4) by analysis of variance yielded a significant difference in block. Although we did not observe any relevant use-dependent block, ajulemic acid induced a strong hyperpolarizing shift of the voltage dependency of fast inactivation and modest shift of slow inactivation. The local anesthetic-insensitive Nav1.5 constructs N406K and F1760A displayed a preserved sensitivity to block by ajulemic acid. Finally, we found that low concentrations of ajulemic acid efficiently inhibited Navß4 peptide-mediated resurgent currents in Nav1.5. CONCLUSIONS: Our data suggest that block of sodium channels can be a relevant mechanism by which ajulemic acid alleviates neuropathic pain. The potent inhibition of resurgent currents and the preserved block on local anesthetic-insensitive channels indicates that ajulemic acid interacts with a conserved but yet unknown site of sodium channels.

The distinct effects of lipid emulsions used for "lipid resuscitation" on gating and bupivacaine-induced inhibition of the cardiac sodium channel Nav1.5.

BACKGROUND: Systemic administration of lipid emulsions is an established treatment for local anesthetic intoxication. However, it is unclear by which mechanisms lipids achieve this function. The high cardiac toxicity of the lipophilic local anesthetic bupivacaine probably results from a long-lasting inhibition of the cardiac Na channel Nav1.5. In this study, we sought to determine whether lipid emulsions functionally interact with Nav1.5 or counteract inhibition by bupivacaine. METHODS: Human embryonic kidney cells expressing human Nav1.5 were investigated by whole-cell patch clamp. The effects of Intralipid® and Lipofundin® were explored on functional properties and on bupivacaine-induced inhibition. RESULTS: Intralipid and Lipofundin did not affect the voltage dependency of activation, but induced a small hyperpolarizing shift of the steady-state fast inactivation and impaired the recovery from fast inactivation. Lipofundin, but not Intralipid, induced a concentration-dependent but voltage-independent tonic block (42% ± 4% by 3% Lipofundin). The half-maximal inhibitory concentration (IC50) values for tonic block by bupivacaine (50 ± 4 µM) were significantly increased when lipids were coapplied (5% Intralipid: 196 ± 22 µM and 5% Lipofundin: 103 ± 8 µM). Use-dependent block by bupivacaine at 10 Hz was also reduced by both lipid emulsions. Moreover, the recovery of inactivated channels from bupivacaine-induced block was faster in the presence of lipids. CONCLUSIONS: Our data indicate that lipid emulsions reduce rather than increase availability of Nav1.5. However, both Intralipid and Lipofundin partly relieve Nav1.5 from block by bupivacaine. These effects are likely to involve not only a direct interaction of lipids with Nav1.5 but also the ability of lipid emulsions to absorb bupivacaine and thus reduce its effective concentration.

4-Chloropropofol enhances chloride currents in human hyperekplexic and artificial mutated glycine receptors.

BACKGROUND: The mammalian neurological disorder hereditary hyperekplexia can be attributed to various mutations of strychnine sensitive glycine receptors. The clinical symptoms of "startle disease" predominantly occur in the newborn leading to convulsive hypertonia and an exaggerated startle response to unexpected mild stimuli. Amongst others, point mutations R271Q and R271L in the α1-subunit of strychnine sensitive glycine receptors show reduced glycine sensitivity and cause the clinical symptoms of hyperekplexia.Halogenation has been shown to be a crucial structural determinant for the potency of a phenolic compound to positively modulate glycine receptor function.The aim of this in vitro study was to characterize the effects of 4-chloropropofol (4-chloro-2,6-dimethylphenol) at four glycine receptor mutations. METHODS: Glycine receptor subunits were expressed in HEK 293 cells and experiments were performed using the whole-cell patch-clamp technique. RESULTS: 4-chloropropofol exerted a positive allosteric modulatory effect in a low sub-nanomolar concentration range at the wild type receptor (EC50 value of 0.08 ± 0.02 nM) and in a micromolar concentration range at the mutations (1.3 ± 0.6 µM, 0.1 ± 0.2 µM, 6.0 ± 2.3 µM and 55 ± 28 µM for R271Q, L, K and S267I, respectively). CONCLUSIONS: 4-chloropropofol might be an effective compound for the activation of mutated glycine receptors in experimental models of startle disease.

Negative- versus positive-pressure ventilation in intubated patients with acute respiratory distress syndrome.

INTRODUCTION: Recent experimental data suggest that continuous external negative-pressure ventilation (CENPV) results in better oxygenation and less lung injury than continuous positive-pressure ventilation (CPPV). The effects of CENPV on patients with acute respiratory distress syndrome (ARDS) remain unknown. METHODS: We compared 2 h CENPV in a tankrespirator ("iron lung") with 2 h CPPV. The six intubated patients developed ARDS after pulmonary thrombectomy (n = 1), aspiration (n = 3), sepsis (n = 1) or both (n = 1). We used a tidal volume of 6 ml/kg predicted body weight and matched lung volumes at end expiration. Haemodynamics were assessed using the pulse contour cardiac output (PiCCO) system, and pressure measurements were referenced to atmospheric pressure. RESULTS: CENPV resulted in better oxygenation compared to CPPV (median ratio of arterial oxygen pressure to fraction of inspired oxygen of 345 mmHg (minimum-maximum 183 to 438 mmHg) vs 256 mmHg (minimum-maximum 123 to 419 mmHg) (P < 0.05). Tank pressures were -32.5 cmH2O (minimum-maximum -30 to -43) at end inspiration and -15 cmH2O (minimum-maximum -15 to -19 cmH2O) at end expiration. NO Inspiratory transpulmonary pressures decreased (P = 0.04) and airway pressures were considerably lower at inspiration (-1.5 cmH2O (minimum-maximum -3 to 0 cmH2O) vs 34.5 cmH2O (minimum-maximum 30 to 47 cmH2O), P = 0.03) and expiration (4.5 cmH2O (minimum-maximum 2 to 5) vs 16 cmH2O (minimum-maximum 16 to 23), P =0.03). During CENPV, intraabdominal pressures decreased from 20.5 mmHg (12 to 30 mmHg) to 1 mmHg (minimum-maximum -7 to 5 mmHg) (P = 0.03). Arterial pressures decreased by approximately 10 mmHg and central venous pressures by 18 mmHg. Intrathoracic blood volume indices and cardiac indices increased at the initiation of CENPV by 15% and 20% (P < 0.05), respectively. Heart rate and extravascular lung water indices remained unchanged. CONCLUSIONS: CENPV with a tank respirator improved gas exchange in patients with ARDS at lower transpulmonary, airway and intraabdominal pressures and, at least initially improving haemodynamics. Our observations encourage the consideration of further studies on the physiological effects and the clinical effectiveness of CENPV in patients with ARDS.

Interaction of alfaxalone with the neuronal and the skeletal muscle sodium channel.

The neurosteroid alfaxalone exerts potent anesthetic activity in humans and animals. In former studies on myelinated axons, alfaxalone was assumed to produce a local anesthetic-like effect on the peripheral nervous system. Therefore,the present in vitro study aimed to characterize possible modulatory actions of alfaxalone on voltage-gated sodium channels. -Subunits of voltage-gated neuronal (Nav1.2)and skeletal muscle (Nav1.4) sodium channels were stably expressed in human embryonic kidney cells, and in vitro effects of alfaxalone were compared with lidocaine by means of the patch clamp technique. Alfaxalone preferentially blocked slow inactivated channels and therefore could provide membrane-stabilizing effects in ischemic/hypoxic tissues where slow inactivation is regarded to play a crucial role.

Thyroid gland rupture: a rare case of respiratory distress.

BACKGROUND: Rupture of a normal thyroid gland after blunt cervical trauma is a rare case of airway compression. This case report describes the case of a 79-year-old woman who developed severe respiratory distress after a bicycle crash. CASE REPORT: Presenting about 2 h after the crash, the patient noted cervical swelling and increasing dyspnea. The diagnosis of thyroid gland rupture was made with a combination of computed tomography scan, cervical radiography, and bronchoscopy. Invasive airway management was required in the first few hours after the crash. The patient underwent a left hemithyroidectomy, and recovered without complications. CONCLUSION: This case report highlights the fact that thyroid gland rupture can be a threatening complication of blunt cervical trauma.

Paracetamol fails to positively modulate and directly activate chloride currents in human α1-glycine receptors.

Paracetamol (acetaminophen) is a widely used antipyretic and analgesic drug for mild or moderate pain states. As the primary site of action of paracetamol is still the subject of ongoing discussion, the focus of this study is the investigation of a potential mechanism which might contribute to its beneficial effects in the therapy of pain. Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. In this study we investigated the interaction of paracetamol with strychnine-sensitive α(1)-glycine receptors (α(1)-GlyR). α(1)-GlyR subunits transiently expressed in HEK-293 cells were studied using the whole-cell patch-clamp technique and a piezo-controlled liquid filament fast application system. Paracetamol fails to show a positive allosteric modulatory effect in low nano- to micromolar concentrations and lacks direct activation in micromolar concentrations at the α(1)-GlyR. Consequently, the analgesic actions of paracetamol leading to pain relief appear to be mediated via other mechanisms, but not via activation of spinal glycinergic pathways.

Defective polysialylation and sialylation induce opposite effects on gating of the skeletal Na+ channel NaV1.4 in Chinese hamster ovary cells.

Polysialic acid (polySia) is a large, negatively charged homopolymer of 2,8-linked N-acetylneuraminic acid residues resulting from remodeling and extension of protein-bound sialic acid (Sia) residues and seems to have a key role in regulating neural cell development and function. The aim of this study was to explore and compare the effects of polySia and sialylation on gating of voltage-gated sodium channels. The skeletal muscle α-subunit NaV1.4 was transiently expressed in wild-type Chinese hamster ovary (CHO) cells or in mutant CHO cells with deficits in their capacity to produce sialylated or polysialylated membrane components. Expression in both mutant cell lines resulted in larger peak current amplitudes as compared to wild-type CHO cells. Loss of Sia and polySia also resulted in significant shifts of voltage-dependent activation and steady-state inactivation, however, in opposite directions. Furthermore, only the loss of Sia had a significant effect on recovery from fast inactivation. Our data demonstrate for the first time that gating of voltage-gated sodium channels seems to be differentially regulated by polySia and Sia.

Reduced post-operative neutrophil activation in liver transplant recipients suffering from post-hepatitic cirrhosis.

BACKGROUND: It has been supposed that liver transplant recipients with hepatitis C virus infection have a higher incidence of infectious complications after transplantation. This study was designed to investigate whether neutrophil function is immediately affected by liver transplantation. METHODS: Biochemical values, plasma levels of myeloperoxidase (MPO), hydrogen peroxide production of neutrophils and neutrophil-platelet complexes were analyzed in 32 patients who underwent liver transplantation and 20 healthy volunteers. RESULTS: MPO levels were significantly increased 24 h after reperfusion. In post-hepatitic patients levels were significantly lower three d up to one wk post-transplant than in patients due to other liver diseases. One wk post-operatively the respiratory burst activity following N-formyl-methionyl-leucylphenylalanine (fMLP) or (tumor necrosis factor-alpha) TNF-alpha/fMLP stimulation was depressed in post-hepatitic recipients. Respiratory burst stimulated with phorbol 12-myristate 13-acetate in these patients was increased one wk after transplantation. One d after transplantation the neutrophil-platelet complexes decreased significantly throughout the post-operative period. CONCLUSIONS: The results of this study suggest a reduced post-operative neutrophil activation in liver transplant recipients suffering from post-hepatitic cirrhosis compared to cirrhosis due to other causes. We hypothesized that neutrophil dysfunction in those patients depends on the underlying disease with an increased susceptibility to bacterial or fungal infections.

The non-anaesthetic propofol analogue 2,6-di-tert-butylphenol fails to modulate GABA(A) receptor function.

Modulation of inhibitory synaptic transmission within the central nervous system contributes considerably to the anaesthetic effects of propofol and its analogues in vivo. We have studied the effects of the non-anaesthetic propofol analogue 2,6-di-tert-butylphenol on rat alpha(1)beta(2)gamma(2) GABA(A) receptors expressed in a mammalian expression system (HEK 293 cells) using the whole-cell patch clamp technique. Our experiments showed that 2,6-di-tert-butylphenol completely lacks co-activation and direct activation of the inhibitory GABA(A) receptor. Our results support the assumption that modulation of inhibitory GABA(A) receptor function is responsible for the anaesthetic effects of propofol in vivo.

The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function.

Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. Cannabidiol is a nonpsychotropic plant constituent of Cannabis sativa. As we hypothesized that non-CB receptor mechanisms of cannabidiol might contribute to its anti-inflammatory and neuroprotective effects, we investigated the interaction of cannabidiol with strychnine-sensitive alpha(1 )and alpha(1)beta glycine receptors by using the whole-cell patch clamp technique. Cannabidiol showed a positive allosteric modulating effect in a low micromolar concentration range (EC(50) values: alpha(1) = 12.3 +/- 3.8 micromol/l and alpha(1)beta = 18.1 +/- 6.2 micromol/l). Direct activation of glycine receptors was observed at higher concentrations above 100 micromol/l (EC(50) values: alpha(1) = 132.4 +/- 12.3 micromol/l and alpha(1)beta = 144.3 +/- 22.7 micromol/l). These in vitro results suggest that strychnine-sensitive glycine receptors may be a target for cannabidiol mediating some of its anti-inflammatory and neuroprotective properties.

Modulation of glycine receptor function by the synthetic cannabinoid HU210.

Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. HU210 is a non-psychotropic, synthetic cannabinoid. As we hypothesized that non-CB receptor mechanisms of HU210 might contribute to its anti-inflammatory and anti-nociceptive effects we investigated the interaction of HU210 with strychnine-sensitive alpha(1 )glycine receptors by using the whole-cell patch clamp technique. HU210 showed a positive allosteric modulating effect in a low micromolar concentration range (EC(50): 5.1 +/- 2.6 micromol/l). Direct activation of glycine receptors was observed at higher concentrations above 100 micromol/l (EC(50): 188.7 +/- 46.2 micromol/l). These in vitro results suggest that strychnine-sensitive glycine receptors may be a target for HU210 mediating some of its anti-inflammatory and anti-nociceptive properties.

Endotoxin reduces availability of voltage-gated human skeletal muscle sodium channels at depolarized membrane potentials.

OBJECTIVE: Critical illness myopathy is a common cause for difficulties in weaning from the respirator and prolonged rehabilitation of patients recovering from sepsis. Several studies have shown that the primary cause of acute generalized muscle weakness is loss of muscle membrane excitability. This study was designed to investigate a potential direct interaction of lipopolysaccharides from Escherichia coli with voltage-gated human skeletal muscle sodium channels (NaV1.4) in vitro. DESIGN: In vitro laboratory investigation. SETTING: University laboratory. SUBJECTS: NaV1.4 sodium channel alpha-subunits stably expressed in human embryonic kidney (HEK293) cells. INTERVENTIONS: We investigated the effect of lipopolysaccharide on voltage-dependent sodium channel gating by using two distinct modes of application: 1) acute perfusion (pharmacologic lipopolysaccharide concentrations between 5 ng/mL and 50 microg/mL) in order to establish a concentration-effect relationship; and 2) incubation with a clinically relevant concentration of lipopolysaccharide (300 pg/mL). MEASUREMENTS AND MAIN RESULTS: Lipopolysaccharide did not alter the kinetics of sodium current activation or inactivation when depolarizations were started from hyperpolarized holding potentials. However, when either fast or slow inactivation was induced by membrane depolarization before the test pulse, lipopolysaccharide reversibly reduced channel availability during the test pulse at concentrations of > or = 50 ng/mL revealed by a maximum hyperpolarizing shift of -25 mV in the voltage dependence of fast and slow inactivation, respectively. Incubation with a lipopolysaccharide concentration of 300 pg/mL for 1 hr reproduced the effects on slow but not on fast inactivation. After 20 hrs of low-dose lipopolysaccharide, the peak sodium current was significantly reduced. CONCLUSIONS: Our results show that lipopolysaccharide interacts with voltage-gated sodium channels, reducing channel availability at depolarized membrane potentials during acute application, independent of the membrane potential after chronic exposure. These effects may contribute to reduced muscle membrane excitability in sepsis.

A transmembrane residue influences the interaction of propofol with the strychnine-sensitive glycine alpha1 and alpha1beta receptor.

BACKGROUND: Propofol, well known for its anesthetic effects, acts as a positive allosteric modulator of the alpha-aminobutyric acid type A (GABA(A)) receptor but also enhances the function of the glycine receptor. The GABA modulatory effects of propofol are influenced by an amino acid residue located within the second transmembrane domain (TM2) of the GABA(A) receptor beta subunit. In glycine alpha(1) subunits, the homologous residue (serine 267) affects the glycine modulatory actions of alcohols and alkane anesthetics. In the present study we investigated the role of this residue on the interaction of propofol with the glycine alpha(1) and alpha(1)beta receptor. METHODS: The influence of propofol on wild type and mutant (alpha(1)S267M, alpha(1)S267I, alpha(1)S267Mbeta, alpha(1)S267Ibeta) glycine receptors expressed in human embryonic kidney 293 cells was investigated by using the whole-cell clamp technique. RESULTS: Mutation of the alpha(1) subunit TM2 serine residue to either isoleucine or methionine decreased the sensitivity of the receptor to glycine, and abolished the direct activation of the glycine receptor by propofol. Additionally, the methionine and particularly the isoleucine mutation decreased the glycine-enhancing actions of propofol. CONCLUSIONS: The nature of the TM2 residue (267) of the glycine alpha(1) subunit influences the glycine modulatory effect of propofol and direct activation of the receptor by this anesthetic. A comparison of the impact of such complementary mutations on the interaction of propofol with glycine and GABA(A) receptors should permit a better understanding of the molecular determinants of action of propofol on these structurally related receptors and may aid in the development of selective glycine receptor modulators.

The anaesthetic steroid alphaxalone positively modulates alpha1-glycine receptor function.

Inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the processing of nociceptive signals, and mainly involves glycine. We have studied the effects of alphaxalone on alpha(1) homomeric glycine receptors expressed in a mammalian expression system (HEK 293 cells) using the whole-cell patch-clamp technique. Our experiments showed a coactivating effect of alphaxalone with a concentration for half-maximum activation (EC(50)) of the effect of a low glycine concentration (EC(20)) of 70.9 +/- 21.5 micromol/l. Taking into account the results of other groups, our study suggests that neuroactive steroids might be an interesting class of compounds to probe subunit-specific effects of glycine receptors.

Neurogenic pulmonary edema in a fatal case of subarachnoid hemorrhage.

Neurogenic pulmonary edema (NPE) is caused by a variety of central nervous system lesions and may appear as a subclinical complication. The fulminant form of NPE is always life-threatening. Many pathophysiologic mechanisms have been implicated in the development of NPE, but the exact interaction remains unknown. We report a case of a fulminant NPE with fatal consequences associated with a subarachnoid hemorrhage. Treatment focuses on ventilatory support and measures to reduce intracranial pressure.