Glutathione accelerates sodium channel inactivation in excised rat axonal membrane patches

The effects of glutathione were studied on the gating behaviour of sodium channels in membrane patches of rat axons. Depolarizing pulses from –120 to –40 mV elicited sodium currents of up to 500 pA, indicating the simultaneous activation of up to 250 sodium channels. Inactivation of these channels in the excised, inside-out configuration was fitted by two time constants ( h1=0.81 ms; h2= 5.03 ms) and open time histograms at 0 mV revealed a biexponential distribution of channel openings ( short=0.28 ms; long=3.68 ms). Both, the slow time constant of inactivation and the long lasting single channel openings disappeared after addition of the reducing agent glutathione (2–5 mM) to the bathing solution. Sodium channels of excised patches with glutathione present on the cytoplasmatic face of the membrane had inactivation kinetics similar to channels recorded in the cell-attached configuration. These observations indicate that redox processes may contribute to the gating of axonal sodium channels

In the back of your mind: Cortical mapping of paraspinal afferent inputs

Topographic organisation is a hallmark of vertebrate cortex architecture, characterised by ordered projections of the body's sensory surfaces onto brain systems. High-resolution functional magnetic resonance imaging (fMRI) has proven itself as a valuable tool to investigate the cortical landscape and its (mal-)adaptive plasticity with respect to various body part representations, in particular extremities such as the hand and fingers. Less is known, however, about the cortical representation of the human back. We therefore validated a novel, MRI-compatible method of mapping cortical representations of sensory afferents of the back, using vibrotactile stimulation at varying frequencies and paraspinal locations, in conjunction with fMRI. We expected high-frequency stimulation to be associated with differential neuronal activity in the primary somatosensory cortex (S1) compared with low-frequency stimulation and that somatosensory representations would differ across the thoracolumbar axis. We found significant differences between neural representations of high-frequency and low-frequency stimulation and between representations of thoracic and lumbar paraspinal locations, in several bilateral S1 sub-regions, and in regions of the primary motor cortex (M1). High-frequency stimulation preferentially activated Brodmann Area (BA) regions BA3a and BA4p, whereas low-frequency stimulation was more encoded in BA3b and BA4a. Moreover, we found clear topographic differences in S1 for representations of the upper and lower back during high-frequency stimulation. We present the first neurobiological validation of a method for establishing detailed cortical maps of the human back, which might serve as a novel tool to evaluate the pathological significance of neuroplastic changes in clinical conditions such as chronic low back pain

Wirkungsweise alter und neuer Antikoagulanzien

Die drei häufigsten Indikationen für eine Behandlung mit Hemmern der plasmatischen Gerinnung sind das Vorhofflimmern, die venöse Thromboembolie und valvuläre Kardiopathien. Aufgrund der Häufigkeit dieser Pathologien kann man davon ausgehen, dass rund 1% der Bevölkerung oral antikoaguliert ist. Ungefähr ein Drittel der auf einer chirurgischen Abteilung hospitalisierten Patienten erhält Vitamin-K-Antagonisten. Somit handelt es sich hierbei um eine Behandlungsmodalität, mit der sowohl Grundversorger und Spezialisten in der Praxis als auch Klinikärzte fortwährend konfrontiert sind. Inhibitoren der Gerinnung haben in vielen Situationen einen großen Nutzen gezeigt, welcher allerdings mit einem erhöhten Blutungsrisiko bezahlt sein will. Diese Gratwanderung zwischen einem Zuviel und einem Zuwenig der antikoagulatorischen Wirkung ist eine wichtige Herausforderung in der klinischen Arbeit mit Patienten. Die Kenntnis der der medikamentösen Gerinnungshemmung zugrundeliegenden Mechanismen ist notwendig, um Indikationen für antikoagulatorische Therapien kritisch evaluieren und deren Management effizient steuern zu können. Im Idealfall muss die Sicherstellung einer ausreichenden Hämostase bei gleichzeitiger Vermeidung thrombotischer Ereignisse das Ziel einer adäquaten Gerinnungshemmung sein. Dieser Artikel soll einen Überblick über das Gerinnungssystem und über etablierte, aber auch neue pharmakologische Angriffspunkte bieten. = Atrial fibrillation, venous thromboembolism, and valvular heart disease are the most common indications for treatment with anticoagulants. Regarding the high incidence of these diseases, it can be assumed that about 1% of the population takes oral anticoagulants. Approximately one third of the patients hospitalized in a surgical clinic receive vitamin K antagonists. Hence, general practitioners and specialists in hospitals as well as in private practice are constantly faced with different options of anticoagulatory treatment. In numerous situations, inhibitors of coagulation exhibit a substantial benefit. However, this is only achieved by accepting an increased risk of bleeding. To walk the tightrope between too much and insufficient anticoagulatory action is an important challenge in clinical practice. Knowledge of the mechanisms underlying pharmacological anticoagulation is crucial in order to evaluate the indications for and efficiently manage anticoagulant therapy. Ideally, the aim of an adequate anticoagulation should be to guarantee sufficient hemostasis in combination with simultaneous prevention of thrombus formation. This article intends to provide an overview of the coagulation system and established as well as novel pharmacological targets

BackWards - Unveiling the brain's topographic organization of paraspinal sensory input

Cortical reorganization and its potential pathological significance are being increasingly studied in musculoskeletal disorders such as chronic low back pain (CLBP) patients. However, detailed sensory-topographic maps of the human back are lacking, and a baseline characterization of such representations, reflecting the somatosensory organization of the healthy back, is needed before exploring potential sensory map reorganization. To this end, a novel pneumatic vibrotactile stimulation method was used to stimulate paraspinal sensory afferents, while studying their cortical representations in unprecedented detail. In 41 young healthy participants, vibrotactile stimulations at 20 Hz and 80 Hz were applied bilaterally at nine locations along the thoracolumbar axis while functional magnetic resonance imaging (fMRI) was performed. Model-based whole-brain searchlight representational similarity analysis (RSA) was used to investigate the organizational structure of brain activity patterns evoked by thoracolumbar sensory inputs. A model based on segmental distances best explained the similarity structure of brain activity patterns that were located in different areas of sensorimotor cortices, including the primary somatosensory and motor cortices and parts of the superior parietal cortex, suggesting that these brain areas process sensory input from the back in a "dermatomal" manner. The current findings provide a sound basis for testing the "cortical map reorganization theory" and its pathological relevance in CLBP

Psilocybin Induces Aberrant Prediction Error Processing of Tactile Mismatch Responses—A Simultaneous EEG–FMRI Study

As source of sensory information, the body provides a sense of agency and self/non-self-discrimination. The integration of bodily states and sensory inputs with prior beliefs has been linked to the generation of bodily self-consciousness. The ability to detect surprising tactile stimuli is essential for the survival of an organism and for the formation of mental body representations. Despite the relevance for a variety of psychiatric disorders characterized by altered body and self-perception, the neurobiology of these processes is poorly understood. We therefore investigated the effect of psilocybin (Psi), known to induce alterations in self-experience, on tactile mismatch responses by combining pharmacological manipulations with simultaneous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) recording. Psi reduced activity in response to tactile surprising stimuli in frontal regions, the visual cortex, and the cerebellum. Furthermore, Psi reduced tactile mismatch negativity EEG responses at frontal electrodes, associated with alterations of body- and self-experience. This study provides first evidence that Psi alters the integration of tactile sensory inputs through aberrant prediction error processing and highlights the importance of the 5-HT2A system in tactile deviancy processing as well as in the integration of bodily and self-related stimuli. These findings may have important implications for the treatment of psychiatric disorders characterized by aberrant bodily self-awareness

Pericardial effusion unrelated to surgery is a predictor of mortality in heart transplant patients

Background: Hemodynamically irrelevant pericardial effusion (PeEf) is a predictor of adverse outcome in heart failure patients. The clinical relevance of a PeEf unrelated to surgery in heart transplant patients remains unknown. This study assesses the prognostic value of PeEf occurring later than 1 year after transplantation. Methods: All patients undergoing heart transplantation in Zurich between 1989 and 2012 were screened. Cox proportional hazard models were used to analyze mortality (primary) and hospitalization (secondary endpoint). PeEf time points were compared to baseline for rejection, immunosuppressants, tumors, inflam­mation, heart failure, kidney function, hemodynamic, and echocardiographic parameters. Results: Of 152 patients (mean age 48.3 ± 11.9), 25 developed PeEf. Median follow-up period was 11.9 (IQR 5.8–17) years. The number of deaths was 6 in the PeEf group and 46 in the non-PeEf group. The occurrence of PeEf was associated with a 2.5-fold increased risk of death (HR 2.49, 95% CI 1.02–6.13, p = 0.046) and hospitalization (HR 2.53, 95% CI 1.57–4.1, p = 0.0002). Conclusions: This study reveals that the finding of hemodynamically irrelevant PeEf in heart trans­plant patients is a predictor of adverse outcome, suggesting that a careful clinical assessment is war­ranted in heart transplant patients exhibiting small PeEf

Reduced apparent fiber density in the white matter of premature-born adults

Premature-born adults exhibit lasting white matter alterations as demonstrated by widespread reduction in fractional anisotropy (FA) based on diffusion-weighted imaging (DWI). FA reduction, however, is non-specific for microscopic underpinnings such as aberrant myelination or fiber density (FD). Using recent advances in DWI, we tested the hypothesis of reduced FD in premature-born adults and investigated its link with the degree of prematurity and cognition. 73 premature- and 89 mature-born adults aged 25–27 years underwent single-shell DWI, from which a FD measure was derived using convex optimization modeling for microstructure informed tractography (COMMIT). Premature-born adults exhibited lower FD in numerous tracts including the corpus callosum and corona radiata compared to mature-born adults. These FD alterations were associated with both the degree of prematurity, as assessed via gestational age and birth weight, as well as with reduced cognition as measured by full-scale IQ. Finally, lower FD overlapped with lower FA, suggesting lower FD underlie unspecific FA reductions. Results provide evidence that premature birth leads to lower FD in adulthood which links with lower full-scale IQ. Data suggest that lower FD partly underpins FA reductions of premature birth but that other processes such as hypomyelination might also take place

Smoking in asthma is associated with elevated levels of corticosteroid resistant sputum cytokines—an exploratory study

<p>Background: Current cigarette smoking is associated with reduced acute responses to corticosteroids and worse clinical outcomes in stable chronic asthma. The mechanism by which current smoking promotes this altered behavior is currently unclear. Whilst cytokines can induce corticosteroid insensitivity in-vitro, how current and former smoking affects airway cytokine concentrations and their responses to oral corticosteroids in stable chronic asthma is unclear.</p> <p>Objectives: To examine blood and sputum cytokine concentrations in never, ex and current smokers with asthma before and after oral corticosteroids.</p> <p>Methods: Exploratory study utilizing two weeks of oral dexamethasone (equivalent to 40 mg/day prednisolone) in 22 current, 21 never and 10 ex-smokers with asthma. Induced sputum supernatant and plasma was obtained before and after oral dexamethasone. 25 cytokines were measured by multiplex microbead system (Invitrogen, UK) on a Luminex platform.</p> <p>Results: Smokers with asthma had elevated sputum cytokine interleukin (IL) -6, -7, and -12 concentrations compared to never smokers with asthma. Few sputum cytokine concentrations changed in response to dexamethasone IL-17 and IFNα increased in smokers, CCL4 increased in never smokers and CCL5 and CXCL10 reduced in ex-smokers with asthma. Ex-smokers with asthma appeared to have evidence of an ongoing corticosteroid resistant elevation of cytokines despite smoking cessation. Several plasma cytokines were lower in smokers wi</p> <p>Conclusion: Cigarette smoking in asthma is associated with a corticosteroid insensitive increase in multiple airway cytokines. Distinct airway cytokine profiles are present in current smokers and never smokers with asthma and could provide an explanatory mechanism for the altered clinical behavior observed in smokers with asthma.</p&gt

White matter alterations in chronic MDMA use: Evidence from diffusion tensor imaging and neurofilament light chain blood levels

3,4–Methylenedioxymethamphetamine (MDMA, “Ecstasy”) is a serotonin- and noradrenaline-releasing substance, currently among the most widely used illicit substances worldwide. In animal studies, repeated exposure to MDMA has been associated with dendritic but also axonal degeneration in the brain. However, translation of the axonal findings, specifically, to humans has been repeatedly questioned and the few existing studies investigating white matter alterations in human chronic MDMA users have yielded conflicting findings. In this study, we combined whole-brain diffusion tensor imaging and neurofilament light chain (NfL) analysis in blood to reveal potential MDMA-induced axonal neuropathology. To this end, we assessed 39 chronic MDMA users and 39 matched MDMA-naïve healthy controls. MDMA users showed increased fractional anisotropy in several white matter tracts, most prominently in the corpus callosum as well as corticospinal tracts, with these findings partly related to MDMA use intensity. However, the NfL levels of MDMA users were not significantly different from those of controls. We conclude that MDMA use is not associated with significant white matter lesions due to the absence of reduced fractional anisotropy and increased NfL levels commonly observed in conditions associated with white matter lesions, including stimulant and ketamine use disorders. Hence, the MDMA-induced axonal degradation demonstrated in animal models was not observed in this human study of chronic MDMA users

White matter alterations in chronic MDMA use: Evidence from diffusion tensor imaging and neurofilament light chain blood levels.

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") is a serotonin- and noradrenaline-releasing substance, currently among the most widely used illicit substances worldwide. In animal studies, repeated exposure to MDMA has been associated with dendritic but also axonal degeneration in the brain. However, translation of the axonal findings, specifically, to humans has been repeatedly questioned and the few existing studies investigating white matter alterations in human chronic MDMA users have yielded conflicting findings. In this study, we combined whole-brain diffusion tensor imaging and neurofilament light chain (NfL) analysis in blood to reveal potential MDMA-induced axonal neuropathology. To this end, we assessed 39 chronic MDMA users and 39 matched MDMA-naïve healthy controls. MDMA users showed increased fractional anisotropy in several white matter tracts, most prominently in the corpus callosum as well as corticospinal tracts, with these findings partly related to MDMA use intensity. However, the NfL levels of MDMA users were not significantly different from those of controls. We conclude that MDMA use is not associated with significant white matter lesions due to the absence of reduced fractional anisotropy and increased NfL levels commonly observed in conditions associated with white matter lesions, including stimulant and ketamine use disorders. Hence, the MDMA-induced axonal degradation demonstrated in animal models was not observed in this human study of chronic MDMA users