Explore the vast range of titles available.

Spinal cord injuries often occur at the cervical level above the phrenic motor pools, which innervate the diaphragm. The effects of impaired breathing are a leading cause of death from spinal cord injuries, underscoring the importance of developing strategies to restore respiratory activity. Here we show that, after cervical spinal cord injury, the expression of chondroitin sulphate proteoglycans (CSPGs) associated with the perineuronal net (PNN) is upregulated around the phrenic motor neurons. Digestion of these potently inhibitory extracellular matrix molecules with chondroitinase ABC (denoted ChABC) could, by itself, promote the plasticity of tracts that were spared and restore limited activity to the paralysed diaphragm. However, when combined with a peripheral nerve autograft, ChABC treatment resulted in lengthy regeneration of serotonin-containing axons and other bulbospinal fibres and remarkable recovery of diaphragmatic function. After recovery and initial transection of the graft bridge, there was an unusual, overall increase in tonic electromyographic activity of the diaphragm, suggesting that considerable remodelling of the spinal cord circuitry occurs after regeneration. This increase was followed by complete elimination of the restored activity, proving that regeneration is crucial for the return of function. Overall, these experiments present a way to markedly restore the function of a single muscle after debilitating trauma to the central nervous system, through both promoting the plasticity of spared tracts and regenerating essential pathways. Axonal regeneration after spinal injury Patients with spinal cord injuries in the neck area often need mechanical ventilators to help them breathe, and impaired breathing is a leading cause of death in these patients. Two factors combine to make recovery difficult. First, an injury above the fourth cervical vertebra disrupts the passage of nerve impulses from the respiratory centre in the brainstem to the phrenic motor nuclei in the spinal cord, and second, in the event of injury, adult spinal cord axons tend not to regenerate. Working in a rat model of spinal cord injury, Jerry Silver and colleagues have identified an upregulation of extracellular matrix molecules that impairs axonal regeneration following injury. Using a strategy of specific extracellular component digestion with chondroitinase, combined with peripheral nerve autografting across the damaged section of the spinal cord, the authors demonstrate a significant recovery of respiratory activity after axon regeneration. This study suggests that regeneration and restoration of diaphragm function may be possible after some types of spinal cord trauma.

Cholesterol is one of the major components of plasma membrane, where its distribution is nonhomogeneous and it participates in lipid raft formation. In skeletal muscle cholesterol and lipid rafts seem to be important for excitation-contraction coupling and for neuromuscular transmission, involving cholesterol-rich synaptic vesicles. In the present study, nerve and muscle stimulation-evoked contractions were recorded to assess the role of cholesterol in contractile function of mouse diaphragm. Exposure to cholesterol oxidase (0.2 U/ml) and cholesterol-depleting agent methyl-β-cyclodextrin (1 mM) did not affect markedly contractile responses to both direct and indirect stimulation at low and high frequency. However, methyl-β-cyclodextrin at high concentration (10 mM) strongly decreased the force of both single and tetanus contractions induced by phrenic nerve stimulation. This decline in contractile function was more profoundly expressed when methyl-β-cyclodextrin application was combined with phrenic nerve activation. At the same time, 10 mM methyl-β-cyclodextrin had no effect on contractions upon direct muscle stimulation at low and high frequency. Thus, strong cholesterol depletion suppresses contractile function mainly due to disturbance of the neuromuscular communication, whereas muscle fiber contractility remains resistant to decline.

Impaired respiratory motor output contributes to morbidity and mortality in many neurodegenerative diseases and neurologic injuries. We investigated if expressing designer receptors exclusively activated by designer drugs (DREADDs) in the mid-cervical spinal cord could effectively stimulate phrenic motor output to increase diaphragm activation. Two primary questions were addressed: (1) does effective DREADD-mediated diaphragm activation require focal expression in phrenic motoneurons (vs. non-specific mid-cervical expression), and (2) can this method produce a sustained increase in inspiratory tidal volume? Wild-type (C57Bl/6) and ChAT-Cre mice received bilateral intraspinal (C4) injections of an adeno-associated virus (AAV) encoding the hM3D(Gq) excitatory DREADD. In wild-type mice, this produced non-specific DREADD expression throughout the mid-cervical ventral horn. In ChAT-Cre mice, a Cre-dependent viral construct was used to drive neuronal DREADD expression in the C4 ventral horns, targeting phrenic motoneurons. Diaphragm electromyograms (EMG) were recorded in isoflurane-anesthetized spontaneously breathing mice at 4–9 weeks post-AAV delivery. The DREADD ligand JHU37160 (J60) caused a bilateral, sustained (>1 hr) increase in inspiratory EMG bursting in both groups; the relative increase was greater in ChAT-Cre mice. Additional experiments in ChAT-Cre rats were conducted to determine if spinal DREADD activation could increase inspiratory tidal volume during spontaneous breathing, assessed using whole-body plethysmography without anesthesia. Three to four months after intraspinal (C4) injection of AAV driving Cre-dependent hM3D(Gq) expression, intravenous J60 resulted in a sustained (>30 min) increase in tidal volume. Subsequently, phrenic nerve recordings performed under urethane anesthesia confirmed that J60 evoked a >200% increase in inspiratory output. We conclude that targeting mid-cervical spinal DREADD expression to the phrenic motoneuron pool enables ligand-induced, sustained increases in phrenic motor output and tidal volume. Further development of this technology may enable application to clinical conditions associated with impaired diaphragm activation and hypoventilation.

Objective: To report a new patient friendly and convenient technique for phrenic nerve conduction with alternative sites of stimulation and recording. Methods: Phrenic nerve conduction was performed in forty volunteers and ten patients of peripheral neuropathy. Active recording electrode was placed in tenth intercostal space 2.5 cm away from para-spinal muscles (mid-scapular line), reference electrode in eighth intercostal space just medial to subcostal margin with ground between stimulating and recording electrode. Stimulation was done at the level of crico-thyroid space near or under the posterior margin of sternocleidomastoid muscle. This new method was compared with existing ones. Analysis: Data was analysed using SPSS 23 version. Correlation between height, weight, body mass index, age, and chest expansion was done using bi-variate correlation. Mean latency and amplitude of the study method were compared with other methods using MANNOVA test. Results: Total of forty subjects were studied. Thirty-seven were male subjects. Mean age was 28.03 ± 9.63 years, height 168.0 ± 9.60 cm and chest expansion 3.53 ± 0.64 cm. Right sided phrenic nerve mean latency was 5.99 ± 0.629 ms and amplitude 1.088 ± 0.178 mV. Left sided phrenic nerve conductions showed mean latency of 6.02 ± 1.82 ms, amplitude of 1.092 ± 0.2912 mV. These standard deviations were smaller than what were observed with other methods suggesting increased consistency of our results. There was no correlation between phrenic nerve conduction with age, height, gender or chest expansion. Conclusion: This study method gave a better as well as consistent morphology, higher amplitude and required lower amount of current strength. It was superior to previously reported methods in consistency of normative data.

Thoracic surgery rapidly induces weakness in human diaphragm fibers. The dysfunction is thought to arise from combined effects of the surgical procedures and inactivity. This project tested whether brief bouts of intraoperative hemidiaphragm stimulation would mitigate slow and fast fiber loss of force in the human diaphragm. We reasoned that maintenance of diaphragm activity with brief bouts of intraoperative phrenic stimulation would mitigate diaphragm fiber weakness and myofilament protein derangements caused by thoracic surgery. Nineteen adults (9 females, age 59 ± 12 years) with normal inspiratory strength or spirometry consented to participate. Unilateral phrenic twitch stimulation (twitch duration 1.5 ms, frequency 0.5 Hz, current 2x the motor threshold, max 25 mA) was applied for one minute, every 30 minutes during cardiothoracic surgery. Thirty minutes following the last stimulation bout, biopsies were obtained from the hemidiaphragms for single fiber force mechanics and quantitation of myofilament proteins (abundance and phosphorylation) and compared by a linear mixed model and paired t-test, respectively. Subjects underwent 6 ± 2 hemidiaphragm stimulations at 17 ± 6 mA, during 278 ± 68 minutes of surgery. Longer-duration surgeries were associated with a progressive decline in diaphragm fiber force (p < 0.001). In slow-twitch fibers, phrenic stimulation increased absolute force (+25%, p < 0.0001), cross-sectional area (+16%, p < 0.0001) and specific force (+7%, p < 0.0005). Stimulation did not alter contractile function of fast-twitch fibers, calcium-sensitivity in either fiber type, and abundance and phosphorylation of myofilament proteins. In adults without preoperative weakness or lung dysfunction, unilateral phrenic stimulation mitigated diaphragm slow fiber weakness caused by thoracic surgery, but had no effect on myofilament protein abundance or phosphorylation.

Background and purpose Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). The impact of diabetes mellitus (DM) on respiratory function of ALS patients is uncertain. Methods A retrospective cohort study was carried out. From the 1710 patients with motor neuron disease followed in our unit, ALS and progressive muscular atrophy patients were included. We recorded demographic characteristics, functional ALS rating scale (Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised [ALSFRS‐R]) and its subscores at first visit, respiratory function tests, arterial blood gases, phrenic nerve amplitude (PhrenAmpl), and mean nocturnal oxygen saturation (SpO2mean). We excluded patients with other relevant diseases. Two subgroups were analysed: DIAB (patients with DM) and noDIAB (patients without DM). Independent t‐test, χ2, or Fisher exact test was applied. Binomial logistic regression analyses assessed DM effects. Kaplan–Meier analysis assessed survival. p < 0.05 was considered significant. Results We included 1639 patients (922 men, mean onset age = 62.5 ± 12.6 years, mean disease duration = 18.1 ± 22.0 months). Mean survival was 43.3 ± 40.7 months. More men had DM (p = 0.021). Disease duration was similar between groups (p = 0.063). Time to noninvasive ventilation (NIV) was shorter in DIAB (p = 0.004); total survival was similar. No differences were seen for ALSFRS‐R or its decay rate. At entry, DIAB patients were older (p < 0.001), with lower forced vital capacity (p = 0.001), arterial oxygen pressure (p = 0.01), PhrenAmpl (p < 0.001), and SpO2mean (p = 0.014). Conclusions ALS patients with DM had increased risk of respiratory impairment and should be closely monitored. Early NIV allowed for similar survival rate between groups.

A rare but important complication after lung transplantation (LTx) is postoperative phrenic nerve dysfunction (PND). Diaphragmatic plication (DP) is a well-established treatment option for PND, however, the long-term effect of PND and DP on lung function parameters and survival after LTx are currently unknown. We retrospectively reviewed 1400 LTx recipients transplanted at Medical University of Vienna between 01/2003 and 12/2022. Fluoroscopy and/or phrenic nerve conduction studies confirmed PND when chest radiographs after extubation showed a unilateral heightened diaphragm. We identified 25 patients with post-operative PND, of whom 12 underwent DP. The remaining 1,375 patients served as a control group. Median ICU-stay and hospital-stay were significantly longer in the PND groups (DP: 20 and 57 days; non-DP: 27 and 43 days; control group: 7 and 25 days; P = 0.001/ P < 0.001). PND led to consistently lower %TLC in lung function tests performed within the first three years after LTx. DP was associated with lower %FEV1.0 early after LTx but it aligned to %FEV1.0 of the other groups during follow-up. Although PND significantly affected postoperative recovery after LTx, it did not impair long-term survival outcomes.

In light of the present therapeutic situation in COVID-19, any measure to improve course and outcome of seriously affected individuals is of utmost importance. We recap here evidence that supports the use of human recombinant erythropoietin (EPO) for ameliorating course and outcome of seriously ill COVID-19 patients. This brief expert review grounds on available subject-relevant literature searched until May 14, 2020, including Medline, Google Scholar, and preprint servers. We delineate in brief sections, each introduced by a summary of respective COVID-19 references, how EPO may target a number of the gravest sequelae of these patients. EPO is expected to: (1) improve respiration at several levels including lung, brainstem, spinal cord and respiratory muscles; (2) counteract overshooting inflammation caused by cytokine storm/ inflammasome; (3) act neuroprotective and neuroregenerative in brain and peripheral nervous system. Based on this accumulating experimental and clinical evidence, we finally provide the research design for a double-blind placebo-controlled randomized clinical trial including severely affected patients, which is planned to start shortly.

Objective: This study aimed to analyze the cases of phrenic nerve injury caused by the percutaneous microwave ablation of lung tumors conducted at our center and to explore the risk factors. Materials and Methods: The data of 455 patients who underwent the percutaneous microwave ablation of lung tumors at the Department of Interventional Radiology, First Affiliated Hospital of Fujian Medical University from July 2017 to October 2021, were retrospectively analyzed. The cases of phrenic nerve injury after the percutaneous ablation were reported to analyze the risk factors involved, such as the shortest distance between tumor margin and phrenic nerve, tumor size, and ablation energy. The groups were divided based on the shortest distance between the tumor edge and the phrenic nerve into group 1, d ≤ l cm; group 2, 1 < d ≤2 cm; and group 3, d >2 cm. Lesions with a distance ≤2 cm were compared in terms of tumor size and ablation energy. Results: Among the 455 patients included in this study, 348 had primary lung cancer, and 107 had oligometastatic cancer. A total of 579 lesions were detected, with maximum diameter of 1.27 ± 0.55 cm, and the ablation energy was 9,000 (4,800-72,000) J. Six patients developed phrenic nerve injury, with an incidence of 1.32%. For these six patients, the shortest distance from the lesion edge to the phrenic nerve was 0.75 ± 0.48 cm, and the ablation energy was 10,500 (8,400-34,650) J. There were statistically significant differences in phrenic nerve injury among groups 1, 2, and 3 (P < 0.05). In patients with a distance (d) ≤ 2 cm, there were no significant differences in tumor diameter and energy between the phrenic nerve injury group and the non-injury group (P = 0.80; P = 0.41). In five out of six patients, the diaphragm level completely recovered to the pre-procedure state, and the recovery time of the phrenic nerve was 9.60 ± 5.60 months. Another one was re-examined 11 months after the procedure, and the level of the diaphragm on the affected side had partially recovered. Conclusions: Phrenic nerve injury is a rare but not negligible complication of thermal ablation and is more likely to occur in lesions with a distance ≤2 cm from the phrenic nerve.

BackgroundPhrenic nerve injury (PNI) is one of the common complications in atrial fibrillation (AF) ablation, which often recovers spontaneously. However, the course of its recovery has not been examined fully, especially in regard to the different ablation methods. We sought to compare the recovery course of PNI in cryoballoon, laser balloon, and radiofrequency ablation.MethodsThis multicenter retrospective study analyzed 355 patients who suffered from PNI during AF ablation. PNI occurred during cryoballoon ablation (CB group) and laser balloon ablation (LB group) for a pulmonary vein isolation in 288 and 20 patients, and radiofrequency ablation for a superior vena cava (SVC) isolation (RF-SVC group) in 47 patients, respectivelyResultsThere was a significant difference in the estimated probability of PNI recovery after the procedure between the methods (p = 0.01). PNI recovered significantly earlier in the CB group, especially within 24 h and 3 months post-procedure (the percentage of the recovery within 24 h and 3 months: 49.7% and 71.5% in the CB group, 15.0% and 22.2% in the LB group, and 23.4% and 41.9% in the RF-SVC group, respectively). Persistent PNI after 12 months was observed in only seven patients in the CB group, one in the LB group, and four in the RF-SVC group, respectively.ConclusionPNI rarely persists over 12 months after AF ablation; however, there is a difference in the timing of its recovery. PNI recovers quicker with cryoballoon ablation than with laser balloon ablation or radiofrequency ablation of the SVC.