A simple device to inject indicator gas for wash-out tests during mechanical ventilation

Objective: To evaluate a simple device which injects a constant fraction of indicator gas to the inspiratory mixture for performing multi-breath wash-out tests during controlled ventilation. Design: the technique in which the indicator gas is injected at the mouth of the patient (post-mix) is compared with the technique where the indicator gas is administered in the bellows of the ventilator (pre-mix). Setting: Surgical Intensive Care Unit of a University Hospital. Patients: 10 post-operative mechanically ventilated patients. Interventions: None. Measurements and results: 3 wash-out tests with the post-mix and 3 wash-out tests with the pre-mix method were performed within an hour on every patient. The calculated mean end expiratory lung volume (EEV) was 1.91±0.871 with the post-mix technique and 1.89±0.881 with the premix technique. There was a good agreement with a mean difference of -1.9±6.5% in the calculated EEV values by the two different techniques. Conclusion: The described injector is an affordable device, is easy to assemble and can be incorporated in most electronically regulated ventilators to perform multi-breath indicator gas wash-out tests for pulmonary monitoring at the bed side of ICU patients

Heterogeneous Cortical Effects of Spinal Cord Stimulation

Objectives: The understanding of the cortical effects of spinal cord stimulation (SCS) remains limited. Multiple studies have investigated the effects of SCS in resting-state electroencephalography. However, owing to the large variation in reported outcomes, we aimed to describe the differential cortical responses between two types of SCS and between responders and nonresponders using magnetoencephalography (MEG). Materials and Methods: We conducted 5-minute resting-state MEG recordings in 25 patients with chronic pain with active SCS in three sessions, each after a one-week exposure to tonic, burst, or sham SCS. We extracted six spectral features from the measured neurophysiological signals: the alpha peak frequency; alpha power ratio (power 7–9 Hz/power 9–11 Hz); and average power in the theta (4–7.5 Hz), alpha (8–12.5 Hz), beta (13–30 Hz), and low-gamma (30.5–60 Hz) frequency bands. We compared these features (using nonparametric permutation t-tests) for MEG sensor and cortical map effects across stimulation paradigms, between participants who reported low (&lt; 5, responders) vs high (≥ 5, nonresponders) pain scores, and in three representative participants. Results: We found statistically significant (p &lt; 0.05, false discovery rate corrected) increased MEG sensor signal power below 3 Hz in response to burst SCS compared with tonic and sham SCS. We did not find statistically significant differences (all p &gt; 0.05) between the power spectra of responders and nonresponders. Our data did not show statistically significant differences in the spectral features of interest among the three stimulation paradigms or between responders and nonresponders. These results were confirmed by the MEG cortical maps. However, we did identify certain trends in the MEG source maps for all comparisons and several features, with substantial variation across participants. Conclusions: The considerable variation in cortical responses to the various SCS treatment options necessitates studies with sample sizes larger than commonly reported in the field and more personalized treatment plans. Studies with a finer stratification between responders and nonresponders are required to advance the knowledge on SCS treatment effects.</p

The Effect of Various Spinal Neurostimulation Paradigms on the Supraspinal Somatosensory Evoked Response:A Systematic Review

Introduction: Spinal neurostimulation is a therapy for otherwise intractable chronic pain. Spinal neurostimulation includes stimulation of the spinal cord (SCS), dorsal root ganglion (DRGS), and dorsal root entry zone (DREZS). New paresthesia-free neurostimulation paradigms may rely on different mechanisms of action from those of conventional tonic neurostimulation. The aim of this systematic review is to assess the existing knowledge on the effect of spinal neurostimulation on somatosensory processing in patients with chronic pain. We therefore reviewed the existing literature on the effect of various spinal neurostimulation paradigms on the supraspinal somatosensory evoked response (SER). Materials and Methods: Multiple scientific data bases were searched for studies that assessed the effect of spinal neurostimulation on the supraspinal SER, evoked by painful or nonpainful peripheral stimuli in patients with chronic pain. We found 205 studies, of which 24 were included. Demographic data, study design, and study outcome were extracted. Results: Of the 24 included studies, 23 used electroencephalography to assess the SER; one study used magnetoencephalography. Fifteen studies evaluated tonic SCS; six studies (also) evaluated paresthesia-free paradigms; three studies evaluated the effect of tonic DRGS or DREZS. Sixteen studies used nonpainful stimuli to elicit the SER, 14 observed a decreased SER amplitude. Ten studies used painful stimuli to elicit the SER, yielding mixed results. Discussion: The included studies suggest that both paresthesia-based and paresthesia-free spinal neurostimulation paradigms can decrease (part of) the SER elicited by a nonpainful peripheral stimulus. The observed SER amplitude reduction likely is the effect of various spinal and supraspinal mechanisms of spinal neurostimulation that also contribute to pain relief. Conclusions: Spinal neurostimulation modulates the processing of a peripherally applied nonpainful stimulus. For painful stimuli, the results are not conclusive. It is not yet clear whether paresthesia-free neurostimulation affects the SER differently from paresthesia-based neurostimulation.</p

Calpain cleavage and subcellular characterisation of the ferlin family.

The ferlins are a family of C2-domain containing proteins. C2 domains regulate vesicle fusion in synaptotagmins, and animal models of ferlin deficiency display pathologies related to Ca2+-dependent vesicle fusion. Dysferlin mutations cause limb-girdle muscular dystrophy due to defective membrane repair. Our group has previously shown that Ca2+-dependent proteases, calpains, cleave dysferlin following membrane injury, releasing mini-dysferlinC72, that we hypothesise mediates membrane repair. Otoferlin mutations cause non-syndromic deafness, while no pathology causing mutations have been identified in other ferlins. My project establishes that dysferlin and myoferlin, type-I ferlins, are present at the plasma membrane and endo-lysosomal pathway while otoferlin and Fer1L6, type-II ferlins, are present at the plasma membrane and recycling trans-Golgi compartments. I also show that dysferlin is cleaved to mini-dysferlinC72 following injury in all cell types by the ubiquitous calpains-1 and -2 in the alternatively spliced exon 40a, indicating dysferlin cleavage is a fundamental response to membrane injury. Exon 40a-containing dysferlin recruits to sites of membrane injury in myotubes, indicating mini-dysferlinC72 may function directly at sites of injury. Finally, I have shown that calpains also cleave otoferlin and myoferlin. Cleavage of other ferlins indicates ferlin cleavage is an evolutionarily conserved event, predating the split between type-I and type-II ferlins

Expert Opinion: Exploring the Effectiveness and Tolerability of Capsaicin 179 mg Cutaneous Patch and Pregabalin in the Treatment of Peripheral Neuropathic Pain

Background and Objective: Treatment of peripheral neuropathic pain (PNP) remains a challenge. In the absence of clear predictors of response, clinical decision-making involves trial and error. While many classes of pharmacological agent are used and have shown efficacy, one of the most commonly used first-line treatments is pregabalin. However, in the 60% of PNP cases in which the pain is localized, a local treatment may be more suitable. This article will summarize the evidence for the relative effectiveness and tolerability of the capsaicin 179 mg patch and pregabalin in the treatment of PNP and highlight the expert opinion of the authors based on their own clinical experiences. Results: When compared in a head-to-head trial in patients with PNP, capsaicin 179 mg patch provided non-inferior pain relief compared with an optimized dose of pregabalin, as well as a reduction in dynamic mechanical allodynia, faster onset of action, fewer systemic side effects, and greater treatment satisfaction. Adverse events associated with capsaicin patch are mainly application site reactions, compared with systemic and central nervous system effects with pregabalin. Studies indicate that capsaicin 179 mg patch is associated with a lower burden of therapy than pregabalin in terms of improved tolerability, lack of a daily pill burden, lack of drug–drug interactions, and increased regimen flexibility. Conclusion: In localized neuropathic pain, evidence supports a pragmatic approach of using a local treatment before considering a systemic treatment. For treatment selection, the patient profile (eg, concomitant medication use, age) and the treatments’ efficacy and tolerability profiles should be considered