On regeneration and collateral sprouting to hind limb digits after sciatic nerve injury in the rat

This study examines the proportions of regenerative and collateral sprouting to the skin after peripheral nerve injury. Methods: In the first experimental paradigm, primary afferent neurones were pre-labelled with Diamidino Yellow (DY), injected in digit 3, followed by sciatic nerve section and repair. After three months of regeneration, digit 3 was re-injected with Fast Blue (FB) to label regernating cells. Fluoro-Gold (FG) was applied to the femoral (FEM) and musculocutaneous (MC) nervers four days later to quantify their contribution to the innveration. In the second experimental paradigm, sciatic nerve was first sectioned and repaired. Three months later, the sciatic was resected, and digit 3 injected with FB. After four more days, FEM and MC were resected and FG injected in all digits. Results: Neurones in dorsal root ganglion (DRG) L5 had a higher rate of correct reinnervation of digit 3 (44-72%) than neurones in DRG L4 (14-44%). Like in control cases, only occasional axons were traced from the FEM and MC. In the second experiment, only occasional labelled neurones appeared. Conclusions: The results indicate differences in the capacity for correct peripheral sensory reinnvervation between segmental levels and that in this model collateral sprouting was practically non-existent compared to regenerative sprouting.

Fast Blue and Diamidino Yellow as retrograde tracers in peripheral nerves: efficacy of combined nerve injection and capsule application to transected nerves in the adult rat

Capsule application of Diamidino Yellow (DY) to the cut end of the sciatic nerve immediately followed by capsule application of Fast Blue (FB) resulted in approximate to 95% double-labelled dorsal root ganglion neurones (DRGn) and motoneurones (Mn). Nerve injection of DY followed either immediately or 2 months later by capsule application of FB resulted in approximate to 90% double-labelled DRGn and Mn, indicating that DY and FB label similar populations of DRGn and Mn, and that insignificant DY fading occurred during this period. Inversing the order of application, however, i.e. nerve injection of FB followed immediately by capsule application of DY, resulted in double labelling in only approximate to 10% of the DRGn and Mn. These percentages increased to 70% of the DRGn and 60% of the Mn when the FB injection was followed 1 or 2 months after by the DY application, indicating that DY uptake is blocked by recent administration of FB. The results indicate that DY and FB might be useful for sequential labelling before and after nerve injury as a tool to investigate the accuracy of sensory and motor regeneration.

Contribution of femoral and proximal sciatic nerve branches to the sensory innervation of hindlimb digits in the rat

The present study was performed to investigate the possibility of 'aberrant' innervation of the tips of the hindlimb digits in the rat, i.e., from other sources than the femoral and the main sciatic branches (tibial, peroneal, sural). Cutaneous injections of fluorescent tracers in the digits were combined with either selective nerve transections to restrict afferent routes followed by detection of labeled neurons in dorsal root ganglia (DRGs), or by a delayed application of a second tracer to afferent nerves under study to detect double labeled neurons in DRGs. The results show that the tips of the digits were represented in DRGs L3-6. The femoral nerve afferents from digits 1 and 2 projected primarily to DRG L3 and to a smaller extent to DRG L4. A small number of neurons from primarily medial digits 1 and 2, but also from lateral digits 3-5, were found to project to DRGs L4 and L5 via a proximal branch that leaves the sciatic nerve near the sciatic notch and runs distally in the posterior part of the thigh, here called the musculocutaneous nerve of the hindlimb. We also have some evidence indicating innervation of the tips of the digits from the posterior cutaneous nerve of the thigh. Aberrant innervation such as that described here might contribute to remaining and perhaps abnormal sensibility after nerve injury and is of interest for the interpretation of results in experimental studies of collateral and regenerative sprouting after such injury

Sciatic and femoral nerve sensory neurones occupy different regions of the L4 dorsal root ganglion in the adult rat.

The topographical distribution of sciatic and femoral nerve sensory neuronal somata in the L4 dorsal root ganglion of the adult rat was mapped after retrograde tracing with one or two of the dyes Fast Blue, Fluoro-Gold, or Diamidino Yellow. The tracers were applied to the proximal transected end of either nerve alone, or from both nerves in the same animal using separate tracers. Three-dimensional reconstructions of the distribution of labelled neurones were made from serial sections of the L4 dorsal root ganglion which is the only ganglion that these two nerves share. The results showed that with little overlap, femoral nerve neurones distribute dorsally and rostrally whereas sciatic nerve neurones distribute medially and ventrally. This finding indicates the existence of a somatotopical organisation for the representation of different peripheral nerves in dorsal root ganglia of adult animals.

Comparison of electrical nerve stimulation, electrical muscle stimulation and magnetic nerve stimulation to assess the neuromuscular function of the plantar flexor muscles.

INTRODUCTION: As it might lead to less discomfort, magnetic nerve stimulation (MNS) is increasingly used as an alternative to electrical stimulation methods. Yet, MNS and electrical nerve stimulation (ENS) and electrical muscle stimulation (EMS) have not been formally compared for the evaluation of plantar flexor neuromuscular function. METHODS: We quantified plantar flexor neuromuscular function with ENS, EMS and MNS in 10 volunteers in fresh and fatigued muscles. Central alterations were assessed through changes in voluntary activation level (VAL) and peripheral function through changes in M-wave, twitch and doublet (PS100) amplitudes. Discomfort associated with 100-Hz paired stimuli delivered with each method was evaluated on a 10-cm visual analog scale. RESULTS: VAL, agonist and antagonist M-wave amplitudes and PS100 were similar between the different methods in both fresh and fatigued states. Potentiated peak twitch was lower in EMS compared to ENS, whereas no difference was found between ENS and MNS for any parameter. Discomfort associated with MNS (1.5 ± 1.4 cm) was significantly less compared to ENS (5.5 ± 1.9 cm) and EMS (4.2 ± 2.6 cm) (p < 0.05). CONCLUSION: When PS100 is used to evaluate neuromuscular properties, MNS, EMS and ENS can be used interchangeably for plantar flexor neuromuscular function assessment as they provide similar evaluation of central and peripheral factors in unfatigued and fatigued states. Importantly, electrical current spread to antagonist muscles was similar between the three methods while discomfort from MNS was much less compared to ENS and EMS. MNS may be potentially employed to assess neuromuscular function of plantar flexor muscles in fragile populations.

Aortic blood pressure measured via EIT: investigation of different measurement settings.

Electrical impedance tomography (EIT) allows the measurement of intra-thoracic impedance changes related to cardiovascular activity. As a safe and low-cost imaging modality, EIT is an appealing candidate for non-invasive and continuous haemodynamic monitoring. EIT has recently been shown to allow the assessment of aortic blood pressure via the estimation of the aortic pulse arrival time (PAT). However, finding the aortic signal within EIT image sequences is a challenging task: the signal has a small amplitude and is difficult to locate due to the small size of the aorta and the inherent low spatial resolution of EIT. In order to most reliably detect the aortic signal, our objective was to understand the effect of EIT measurement settings (electrode belt placement, reconstruction algorithm). This paper investigates the influence of three transversal belt placements and two commonly-used difference reconstruction algorithms (Gauss-Newton and GREIT) on the measurement of aortic signals in view of aortic blood pressure estimation via EIT. A magnetic resonance imaging based three-dimensional finite element model of the haemodynamic bio-impedance properties of the human thorax was created. Two simulation experiments were performed with the aim to (1) evaluate the timing error in aortic PAT estimation and (2) quantify the strength of the aortic signal in each pixel of the EIT image sequences. Both experiments reveal better performance for images reconstructed with Gauss-Newton (with a noise figure of 0.5 or above) and a belt placement at the height of the heart or higher. According to the noise-free scenarios simulated, the uncertainty in the analysis of the aortic EIT signal is expected to induce blood pressure errors of at least ± 1.4 mmHg.

Neuropathic Pain Phenotype Does Not Involve the NLRP3 Inflammasome and Its End Product Interleukin-1β in the Mice Spared Nerve Injury Model.

The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is one of the main sources of interleukin-1β (IL-1β) and is involved in several inflammatory-related pathologies. To date, its relationship with pain has not been studied in depth. The aim of our study was to elucidate the role of NLRP3 inflammasome and IL-1β production on neuropathic pain. Results showed that basal pain sensitivity is unaltered in NLRP3-/- mice as well as responses to formalin test. Spared nerve injury (SNI) surgery induced the development of mechanical allodynia and thermal hyperalgesia in a similar way in both genotypes and did not modify mRNA levels of the NLRP3 inflammasome components in the spinal cord. Intrathecal lipopolysaccharide (LPS) injection increases apoptosis-associated speck like protein (ASC), caspase-1 and IL-1β expression in both wildtype and NLRP3-/- mice. Those data suggest that NLRP3 is not involved in neuropathic pain and also that other sources of IL-1β are implicated in neuroinflammatory responses induced by LPS.

Mikrozystisches Makulaödem bei Optikusatrophie: eine Fallserie Microcystic Macular Edema in Optic Nerve Atrophy: A Case Series.

Background:Microcystic macular edema can occur after optic neuropathies of various etiologies, and is easily demonstrated by OCT. We report a cohort of patients with microcystic macular edema. Patients and Methods: All patients with optic neuropathy and microcystic macular edema were enrolled. Demographics, visual function, retinal angiographies and OCT parameters were studied. Results: Nineteen patients (23 eyes) exhibited microcystic macular edema: 10 men/9 women, aged 17-91 years. Etiologies of optic nerve atrophy were compressive (5), inflammatory (4), glaucoma (3), ischemic (3), trauma (2), degenerative (1), and hereditary (1). Median visual acuity was 4/10 (NLP-12/10). Fluorescein angiography showed no leakage. Topography of the microcystic macular edema correlated with near infrared images but with visual field defects in only 26 %. OCT parameters were all abnormal. Conclusions: Microcystic macular edema is a non-specific manifestation from an optic neuropathy of any etiology. The precise mechanism leading to microcystic macular edema remains unknown but trans-synaptic retrograde degeneration with Müller cells dysfunction is likely. Zusammenfassung Hintergrund: Das mikrozystische Makulaödem kann im Rahmen einer Optikusatrophie jeglicher Ätiologie auftreten und ist leicht mit dem OCT zu erkennen. Wir berichten über eine Patientenkohorte mit mikrozystischem Makulaödem. Patienten und Methoden: Alle Patienten mit einer Optikusneuropathie und einem mikrozystischen Makulaödem wurden in diese Studie eingeschlossen. Die Demografie, die Sehfunktion, die Netzhautangiografie und die OCT-Parameter wurden untersucht. Ergebnisse: Neunzehn Patienten (23 Augen) hatten ein mikrozystisches Makulaödem: 10 Männer/9 Frauen im Alter von 17 bis 91 Jahren. Die Ursachen der Optikusatrophie waren Kompressionen (5), Entzündungen (4), Glaukom (3), Ischämien (3), Traumata (2), Degenerationen (1) und genetisch (1). Der mittlere Visus war 0,4 (keine Lichtwahrnehmung 1,2). In der Fluoreszenzangiografie fand sich keine Leckage. Das OCT des mikrozystischen Makulaödems korrelierte immer mit den Infrarot-Bildern (Nahaufnahme), jedoch nur in 26 % mit den Gesichtsfelddefekten. Alle OCT-Parameter waren abnormal. Schlussfolgerungen: Das mikrozystische Makulaödem ist eine unspezifische Manifestation einer Optikusneuropathie jeglicher Ätiologie. Der genaue Mechanismus, der zu einem mikrozystischen Makulaödem führt, ist unbekannt, eine trans-synaptische retrograde Degeneration mit Dysfunktion der Müller-Zellen ist jedoch wahrscheinlich.

Transient ocular motor nerve palsies associated with presumed cranial nerve schwannomas.

BACKGROUND: Cranial nerve schwannomas are radiologically characterized by nodular cranial nerve enhancement on magnetic resonance imaging (MRI). Schwannomas typically present with gradually progressive symptoms, but isolated reports have suggested that schwannomas may cause fluctuating symptoms as well. METHODS: This is a report of ten cases of presumed cranial nerve schwannoma that presented with transient or recurring ocular motor nerve deficits. RESULTS: Schwannomas of the third, fourth, and fifth nerves resulted in fluctuating deficits of all 3 ocular motor nerves. Persistent nodular cranial nerve enhancement was present on sequential MRI studies. Several episodes of transient oculomotor (III) deficts were associated with headaches, mimicking ophthalmoplegic migraine. CONCLUSIONS: Cranial nerve schwannomas may result in relapsing and remitting cranial nerve symptoms.

Prevalence of Acute Coronary Syndrome in Patients Suspected for Pulmonary Embolism or Acute Aortic Syndrome: Rationale for the Triple Rule-out Concept.

BACKGROUND: The aims of the study were to evaluate the prevalence of acute coronary syndrome (ACS) among patients presenting with atypical chest pain who are evaluated for acute aortic syndrome (AAS) or pulmonary embolism (PE) with computed tomoangiography (CTA) and discuss the rationale for the use of triple rule-out (TRO) protocol for triaging these patients. METHODS: This study is a retrospective analysis of patients presenting with atypical chest pain and evaluated with thoracic (CTA), for suspicion of AAS/PE. Two physicians reviewed patient files for demographic characteristics, initial CT and final clinical diagnosis. Patients were classified according to CTA finding into AAS, PE and other diagnoses and according to final clinical diagnosis into AAS, PE, ACS and other diagnoses. RESULTS: Four hundred and sixty-seven patients were evaluated: 396 (84.8%) patients for clinical suspicion of PE and 71 (15.2%) patients for suspicion of AAS. The prevalence of ACS and AAS was low among the PE patients: 5.5% and 0.5% respectively (P = 0.0001), while the prevalence of ACS and PE was 18.3% and 5.6% among AAS patients (P = 0.14 and P = 0.34 respectively). CONCLUSION: The prevalence of ACS and AAS among patients suspected clinically of having PE is limited while the prevalence of ACS and PE among patients suspected clinically of having AAS is significant. Accordingly patients suspected for PE could be evaluated with dedicated PE CTA while those suspected for AAS should still be triaged using TRO protocol.

Peripheral Nerve Repair: Multimodal Comparison of the Long-Term Regenerative Potential of Adipose Tissue-Derived Cells in a Biodegradable Conduit.

Tissue engineering is a popular topic in peripheral nerve repair. Combining a nerve conduit with supporting adipose-derived cells could offer an opportunity to prevent time-consuming Schwann cell culture or the use of an autograft with its donor site morbidity and eventually improve clinical outcome. The aim of this study was to provide a broad overview over promising transplantable cells under equal experimental conditions over a long-term period. A 10-mm gap in the sciatic nerve of female Sprague-Dawley rats (7 groups of 7 animals, 8 weeks old) was bridged through a biodegradable fibrin conduit filled with rat adipose-derived stem cells (rASCs), differentiated rASCs (drASCs), human (h)ASCs from the superficial and deep abdominal layer, human stromal vascular fraction (SVF), or rat Schwann cells, respectively. As a control, we resutured a nerve segment as an autograft. Long-term evaluation was carried out after 12 weeks comprising walking track, morphometric, and MRI analyses. The sciatic functional index was calculated. Cross sections of the nerve, proximal, distal, and in between the two sutures, were analyzed for re-/myelination and axon count. Gastrocnemius muscle weights were compared. MRI proved biodegradation of the conduit. Differentiated rat ASCs performed significantly better than undifferentiated rASCs with less muscle atrophy and superior functional results. Superficial hASCs supported regeneration better than deep hASCs, in line with published in vitro data. The best regeneration potential was achieved by the drASC group when compared with other adipose tissue-derived cells. Considering the ease of procedure from harvesting to transplanting, we conclude that comparison of promising cells for nerve regeneration revealed that particularly differentiated ASCs could be a clinically translatable route toward new methods to enhance peripheral nerve repair.

First Reported Successful Femoral Valve-in-Valve Transcatheter Aortic Valve Replacement Using the Edwards Sapien 3 Valve.

OBJECTIVES: Management of degenerated aortic valve bioprosthesis classically requires redo surgery, but transcatheter aortic valve-in-valve implantation is becoming a valid alternative in selected cases. In the case of a degenerated Mitroflow bioprosthesis, TAVR is associated with an additional challenge due to a specific risk of coronary occlusion. We aimed to assess the safety and feasibility of transfemoral valve-in-valve implantation of the new Edwards Sapien 3 (Edwards Lifesciences) in a degenerated Mitroflow bioprosthesis (Sorin Group, Inc). METHODS: We report here the safety and feasibility of transfemoral valve-in-valve implantation of a 23 mm Edwards Sapien 3 in a degenerated 25 mm Mitroflow valve and describe the specific assessment of the risk of coronary obstruction using a multi-imaging modality. RESULTS: The final result showed an absence of aortic regurgitation and a mean transvalvular gradient of 14 mm Hg. The patient had no major adverse cardiovascular events at 30-day follow-up. CONCLUSION: Transcatheter valve-in-valve implantation of an Edwards Sapien 3 in a degenerated Mitroflow is feasible and safe, considering a careful assessment of the risk of coronary obstruction with Mitroflow bioprosthesis due to leaflets mounted externally to the stent.

Aorto-bronchial and aorto-pulmonary fistulation after thoracic endovascular aortic repair: an analysis from the European Registry of Endovascular Aortic Repair Complications.

OBJECTIVES: To learn upon incidence, underlying mechanisms and effectiveness of treatment strategies in patients with central airway and pulmonary parenchymal aorto-bronchial fistulation after thoracic endovascular aortic repair (TEVAR). METHODS: Analysis of an international multicentre registry (European Registry of Endovascular Aortic Repair Complications) between 2001 and 2012 with a total caseload of 4680 TEVAR procedures (14 centres). RESULTS: Twenty-six patients with a median age of 70 years (interquartile range: 60-77) (35% female) were identified. The incidence of either central airway (aorto-bronchial) or pulmonary parenchymal (aorto-pulmonary) fistulation (ABPF) in the entire cohort after TEVAR in the study period was 0.56% (central airway 58%, peripheral parenchymal 42%). Atherosclerotic aneurysm formation was the leading indication for TEVAR in 15 patients (58%). The incidence of primary endoleaks after initial TEVAR was n = 10 (38%), of these 80% were either type I or type III endoleaks. Fourteen patients (54%) developed central left bronchial tree lesions, 11 patients (42%) pulmonary parenchymal lesions and 1 patient (4%) developed a tracheal lesion. The recognized mechanism of ABPF was external compression of the bronchial tree in 13 patients (50%), the majority being due to endoleak formation, further ischaemia due to extensive coverage of bronchial feeding arteries in 3 patients (12%). Inflammation and graft erosion accounted for 4 patients (30%) each. Cumulative survival during the entire study period was 39%. Among deaths, 71% were attributed to ABPF. There was no difference in survival in patients having either central airway or pulmonary parenchymal ABPF (33 vs 45%, log-rank P = 0.55). Survival with a radical surgical approach was significantly better when compared with any other treatment strategy in terms of overall survival (63 vs 32% and 63 vs 21% at 1 and 2 years, respectively), as well as in terms of fistula-related survival (63 vs 43% and 63 vs 43% at 1 and 2 years, respectively). CONCLUSIONS: ABPF is a rare but highly lethal complication after TEVAR. The leading mechanism behind ABPF seems to be a continuing external compression of either the bronchial tree or left upper lobe parenchyma. In this setting, persisting or newly developing endoleak formation seems to play a crucial role. Prognosis does not differ in patients with central airway or pulmonary parenchymal fistulation. Radical bronchial or pulmonary parenchymal repair in combination with stent graft removal and aortic reconstruction seems to be the most durable treatment strategy.