Phantom limb syndrome: from pathogenesis to treatment. A narrative review.

Phantom Limb Syndrome (PLS) can be defined as the disabling or painful sensation of the presence of a body part that is no longer present after its amputation. Anatomical changes involved in Phantom Limb Syndrome, occurring at peripheral, spinal and brain levels and include the formation of neuromas and scars, dorsal horn sensitization and plasticity, short-term and long-term modifications at molecular and topographical levels. The molecular reorganization processes of Phantom Limb Syndrome include NMDA receptors hyperactivation in the dorsal horn of the spinal column leading to inflammatory mechanisms both at a peripheral and central level. At the brain level, a central role has been recognized for sodium channels, BDNF and adenosine triphosphate receptors. In the paper we discuss current available pharmacological options with a final overview on non-pharmacological options in the pipeline.

Safety and efficacy of endovascular thrombectomy for primary and secondary MeVO.

BACKGROUND: Medium-vessel occlusions (MeVO) are emerging as a new target for endovascular treatment (EVT). Primary MeVO occur de novo, while secondary MeVO arise from large vessel occlusion (LVO) through clot migration or fragmentation - spontaneously, following intravenous thrombolysis or EVT. We aimed to evaluate efficacy and safety of EVT in primary and EVT-induced secondary MeVO. METHODS: Retrospective single-center study on consecutive EVT-treated acute ischemic stroke, from 2019-to-2021. We considered: (1) exclusive-LVO, patients with LVO and - in case of residual distal occlusion - no rescue endovascular procedure; (2) primary MeVO: initial A2, A3, M2 non-dominant, M3, P2, P3 occlusions; (3) EVT-induced secondary MeVO, presenting LVO with subsequent (treated) EVT-induced MeVO. We compared (univariable/multivariable logistic regression) EVT efficacy (eTICI≥2b, 3-month modified Rankin Scale [mRS] 0-2) and safety (EVT-complications [vessel dissection, perforation, persistent-SAH], symptomatic ICH) in all MeVO versus exclusive-LVO, primary MeVO versus exclusive-LVO, EVT-induced secondary MeVO versus exclusive-LVO and EVT-induced secondary MeVO versus primary MeVO. RESULTS: We included 335 patients: 221 (66.0 %) exclusive-LVO and 114 (34.0 %) MeVO (55 [48.2 %] primary, 59 [51.8 %] secondary). Compared to exclusive-LVO, primary MeVO had higher rates of EVT complications (aOR 3.77 [95%CI 1.58-9.00],p=0.003), lower rates of eTICI≥2b (aOR 0.32 [95%CI 0.12-0.88],p=0.027) and mRS 0-2 (aOR 0.28 [95%CI 0.13-0.63],p=0.002). EVT-induced secondary MeVO had no major differences in efficacy and safety outcomes compared to exclusive-LVO, but a better mRS 0-2 (aOR 8.00 [95%CI 2.12-30.17],p=0.002) compared to primary MeVO. CONCLUSIONS: Primary and EVT-induced secondary MeVO showed different safety/efficacy EVT-related profiles. Dedicated randomized data are needed to identify the best acute reperfusion strategy in the two categories.

Reliability of intraoperative visual evoked potentials (iVEPs) in monitoring visual function during endoscopic transsphenoidal surgery.

OBJECTIVE: To refine a reliable and reproducible intraoperative visual evoked potentials (iVEPs) monitoring protocol during endoscopic transsphenoidal surgery. To assess the reliability of baseline iVEPs in predicting preoperative visual status and perioperative iVEP variation in predicting postoperative visual outcome. METHODS: Sixty-four patients harboring tumors of the pituitary region were included. All patients underwent endoscopic endonasal approach (EEA) with iVEPs monitoring, using a totally intravenous anesthetic protocol. Ophthalmological evaluation included visual acuity and visual field studies. RESULTS: Preoperatively, visual acuity was reduced in 86% and visual field in 76.5% of cases. Baseline iVEPs amplitude was significantly correlated with preoperative visual acuity and visual field (p = 0.001 and p = 0.0004, respectively), confirming the reliability of the neurophysiological/anesthetic protocol implemented. Importantly, perioperatively the variation in iVEPs amplitude was significantly correlated with the changes in visual acuity (p < 0.0001) and visual field (p = 0.0013). ROC analysis confirmed that iVEPs are an accurate predictor of perioperiative visual acuity improvement, with a 100% positive predictive value in patients with preoperative vision loss. CONCLUSIONS: iVEPs during EEA is highly reliable in describing preoperative visual function and can accurately predict postoperative vision improvement. SIGNIFICANCE: iVEPs represent a promising resource for carrying out a more effective and safe endoscopic transsphenoidal surgery.

Protection and Disinfection Activities of Oregano and Thyme Essential Oils Encapsulated in Poly(ε-caprolactone) Nanocapsules.

The biocolonization of building materials by microorganisms is one of the main causes of their degradation. Fungi and bacteria products can have an undesirable impact on human health. The protection and disinfection of sandstone and wood materials are of great interest. In this study, we evaluated the protection and disinfection activity of oregano and thyme essential oils encapsulated in poly(ε-caprolactone) nanocapsules (Or-NCs, Th-NCs) against four types of environmental microorganisms: Pleurotus eryngii, Purpureocillium lilacinum (fungal strains), Pseudomonas vancouverensis, and Flavobacterium sp. (bacterial strains). The surfaces of sandstone and whitewood samples were inoculated with these microorganisms before or after applying Or-NCs and Th-NCs. The concentration-dependent effect of Or-NCs and Th-NCs on biofilm viability was determined by the MTT reduction assay. The results showed that Or-NCs and Th-NCs possess effective disinfection and anti-biofilm activity. Diffuse reflectivity measurements revealed no visible color changes of the materials after the application of the nanoencapsulated essential oils.

Evaluation of the treatment options for COVID-19 patients using generalized hesitant fuzzy- multi criteria decision making techniques.

The breakout of the pandemic COVID-19 has affected numerous countries and territories worldwide. As COVID-19 specific medicines yet to be invented, at present the treatment is case specific, hence identification and evaluation of different prevalent treatment options based on various criteria and attributes are very important not only from the point of view of present pandemic but also for futuristic pandemic preparedness. The present study focuses on identifying, evaluation and ranking of treatment options using Multi Criteria Decision Making (MCDM). In this regard, the existing literature, doctors and scientist were interviewed to know the current treatment options in vogue and the scale of their importance with respect to the criteria. The criteria taken are side effect, regime cost, treatment duration, plasma stability, plasma turnover, time of suppression, ease of application, drug-drug interaction, compliance, fever, pneumonia, intensive care, organ failure, macrophage activation syndrome, hemophagocytic syndrome, pregnancy, kidney problem, age. This study extended Hesitant Fuzzy Set (HFS) to Generalized Hesitant Fuzzy Sets (GHFS). Generalized Hesitant Pentagonal Fuzzy Number (GHPFN) is developed. The properties of GHPFN are demonstrated. Two types of GHPFN has been described. The GHPFN (2nd type) along with MCDM tool Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) has been applied to rank the treatment options. The result of the study ranked 'Hydroxychloroquine' as the first alternative followed by, 'Plasma Exchange', 'Tocilizumab', 'Remdesivir' and 'Favipravir'. To check the robustness and steadiness of the proposed methodology, comparative analysis and sensitivity analysis has been conducted.

Modified Sling Technique for Difficult Filter Retrieval.

Caval filters are placed in the inferior vena cava (IVC) to prevent pulmonary thromboembolism in patients with deep vein thrombosis. If there is no indication for thrombo-embolic risk prevention, the filter can be removed to reduce potential filter-related complications. Advanced endovascular techniques are frequently used to retrieve IVC filters. We describe an alternative filter-removal technique for use when standard techniques are not practicable. In our method, the filter hook is embedded within the IVC wall. To retrieve it, a long introducer is inserted; a guidewire and the "loop snare" retrieval system are then advanced through it with a coaxial system and positioned below the filter at the level of the common iliac vein confluence. The guidewire is then passed through the loop, creating a "sling" around the filter which allows the application of traction from the bottom upwards, releasing the hook from the wall. The loop is then held under tension with the filter aligned in the IVC lumen, and the introducer is advanced distally to completely cover the filter, allowing complete retrieval of the filter without damaging the vessel walls. This modified Sling technique is a safe and feasible method for complicated IVC filter retrieval.

Oregano and Thyme Essential Oils Encapsulated in Chitosan Nanoparticles as Effective Antimicrobial Agents against Foodborne Pathogens.

The use of natural compounds with biocidal activity to fight the growth of bacteria responsible for foodborne illness is one of the main research challenges in the food sector. This study reports the preparation and physicochemical characterization of chitosan nanoparticles loaded with Thymus capitatus (Th-CNPs) and Origanum vulgare (Or-CNPs) essential oils. The nanosystems were obtained by ionotropic gelation technique with high encapsulation efficiency (80-83%) and loading capacity (26-27%). Nanoparticles showed a spherical shape, bimodal particle size distribution, and good stability (zeta potential values > 40 mV). The treatment of the nanosuspensions at different temperatures (4 and 40 °C) and storage times (7, 15, 21, and 30 days) did not affect their physicochemical parameters and highlights their reservoir ability for essential oils also under stressful conditions. Both Or-CNPs and Th-CNPs exhibited an enhanced bactericidal activity against foodborne pathogens (S. aureus, E. coli, L. monocytogenes) than pure essential oils. These ecofriendly nanosystems could represent a valid alternative to synthetic preservatives and be of interest for health and food safety.

Six-Month Assessment of a Hand Prosthesis with Intraneural Tactile Feedback.

OBJECTIVE: Hand amputation is a highly disabling event, which significantly affects quality of life. An effective hand replacement can be achieved if the user, in addition to motor functions, is provided with the sensations that are naturally perceived while grasping and moving. Intraneural peripheral electrodes have shown promising results toward the restoration of the sense of touch. However, the long-term usability and clinical relevance of intraneural sensory feedback have not yet been clearly demonstrated. METHODS: To this aim, we performed a 6-month clinical study with 3 transradial amputees who received implants of transverse intrafascicular multichannel electrodes (TIMEs) in their median and ulnar nerves. After calibration, electrical stimulation was delivered through the TIMEs connected to artificial sensors in the digits of a prosthesis to generate sensory feedback, which was then used by the subjects while performing different grasping tasks. RESULTS: All subjects, notwithstanding their important clinical differences, reported stimulation-induced sensations from the phantom hand for the whole duration of the trial. They also successfully integrated the sensory feedback into their motor control strategies while performing experimental tests simulating tasks of real life (with and without the support of vision). Finally, they reported a decrement of their phantom limb pain and a general improvement in mood state. INTERPRETATION: The promising results achieved with all subjects show the feasibility of the use of intraneural stimulation in clinical settings. ANN NEUROL 2019;85:137-154.

Quantum Chemical and Molecular Dynamics Studies of MUC1 Calix[4,8]arene Scaffold Based Anticancer Vaccine Candidates.

Functional antitumor vaccine constructs are the basis for active tumor immunotherapy, which is useful in the treatment of many types of cancers. MUC1 is one key glycoprotein for targeting and designing new strategies for multicomponent vaccines. Two self-adjuvant tetravalent vaccine candidates were prepared by clustering four or eight PDTRP MUC1 core epitope sequences on calixarene scaffolds. In this work, the different activities of two molecules with calix[4]arene and calix[8]arene skeleton are rationalized. Quantum mechanics, docking, and molecular dynamics structural optimization were first carried out followed by metadynamics to calculate the energy profiles. Further insights were obtained by complementarity studies of molecular fields. The molecular modeling results are in strong agreement with the experimental in vivo immunogenicity data. In conclusion, the overall data shows that, in the designing of anticancer vaccines, scaffold flexibility has a pivotal role in obtaining a suitable electrostatic, hydrophobic, and steric complementarity with the biological target.

Sensitivity to temporal parameters of intraneural tactile sensory feedback.

BACKGROUND: Recent studies have shown that neural stimulation can be used to provide artificial sensory feedback to amputees eliciting sensations referred on the amputated hand. The temporal properties of the neural stimulation modulate aspects of evoked sensations that can be exploited in a bidirectional hand prosthesis. METHODS: We previously collected evidence that the derivative of the amplitude of the stimulation (intra-digit temporal dynamics) allows subjects to recognize object compliance and that the time delay among stimuli injected through electrodes implanted in different nerves (inter-digit temporal distance) allows to recognize object shapes. Nevertheless, a detailed characterization of the subjects' sensitivity to variations of intra-digit temporal dynamic and inter-digit temporal distance of the intraneural tactile feedback has not been executed. An exhaustive understanding of the overall potentials and limits of intraneural stimulation to deliver sensory feedback is of paramount importance to bring this approach closer and closer to the natural situation. To this aim, here we asked two trans-radial amputees to identify stimuli with different temporal characteristics delivered to the same active site (intra-digit temporal Dynamic Recognition (DR)) or between two active sites (inter-digit Temporal distance Recognition (TR)). Finally, we compared the results achieved for (simulated) TR with conceptually similar experiments with real objects with one subject. RESULTS: We found that the subjects were able to identify stimuli with temporal differences (perceptual thresholds) larger than 0.25 s for DR and larger than 0.125 s for TR, respectively. Moreover, we also found no statistically significant differences when the subjects were asked to identify three objects during simulated 'open-loop' TR experiments or real 'closed-loop' tests while controlling robotic hand. CONCLUSIONS: This study is a new step towards a more detailed analysis of the overall potentials and limits of intraneural sensory feedback. A full characterization is necessary to develop more advanced prostheses capable of restoring all lost functions and of being perceived more as a natural limb by users.

Preparation of a radiology department in an Italian hospital dedicated to COVID-19 patients.

Preparedness for the ongoing coronavirus disease 2019 (COVID-19) and its spread in Italy called for setting up of adequately equipped and dedicated health facilities to manage sick patients while protecting healthcare workers, uninfected patients, and the community. In our country, in a short time span, the demand for critical care beds exceeded supply. A new sequestered hospital completely dedicated to intensive care (IC) for isolated COVID-19 patients needed to be designed, constructed, and deployed. Along with this new initiative, the new concept of "Pandemic Radiology Unit" was implemented as a practical solution to the emerging crisis, born out of a critical and urgent acute need. The present article describes logistics, planning, and practical design issues for such a pandemic radiology and critical care unit (e.g., space, infection control, safety of healthcare workers, etc.) adopted in the IC Hospital Unit for the care and management of COVID-19 patients.

Topical Delivery of Curcumin by Choline-Calix[4]arene-Based Nanohydrogel Improves Its Therapeutic Effect on a Psoriasis Mouse Model.

Curcumin (CUR) has shown remarkable efficacy in the treatment of skin diseases, but its effective transdermal delivery is still a major challenge and stimulates interest in the design of novel systems for CUR dispersion, preservation, and delivery facilitation to the deeper layers of the skin. The present work aimed to investigate the potential of a nanohydrogel, formed by a micellar choline-calix[4]arene amphiphile (CALIX) and CUR, in the treatment of skin diseases through an imiquimod (IMQ)-induced psoriasis model. Psoriasis plaques are associated with aberrant keratinization, abnormal distribution of tight junctions (TJs) proteins, and enhanced expression of inflammatory markers. The nanohydrogel restored the normal distribution of TJs proteins ZO1 and occludin and reduced the expression of TNF-α and inducible nitric oxide synthetase (iNOS) compared to the untreated IMQ group. The novelty lies in the calix[4]arene-based nanohydrogel as a potential new soft material for the topical skin delivery of CUR. The nanohydrogel, due to its physicochemical and mechanical properties, enhances the drug water-solubility, preserves CUR from rapid degradation, and eases the local skin administration and penetration.

Microneurography as a tool to develop decoding algorithms for peripheral neuro-controlled hand prostheses.

BACKGROUND: The usability of dexterous hand prostheses is still hampered by the lack of natural and effective control strategies. A decoding strategy based on the processing of descending efferent neural signals recorded using peripheral neural interfaces could be a solution to such limitation. Unfortunately, this choice is still restrained by the reduced knowledge of the dynamics of human efferent signals recorded from the nerves and associated to hand movements. FINDINGS: To address this issue, in this work we acquired neural efferent activities from healthy subjects performing hand-related tasks using ultrasound-guided microneurography, a minimally invasive technique, which employs needles, inserted percutaneously, to record from nerve fibers. These signals allowed us to identify neural features correlated with force and velocity of finger movements that were used to decode motor intentions. We developed computational models, which confirmed the potential translatability of these results showing how these neural features hold in absence of feedback and when implantable intrafascicular recording, rather than microneurography, is performed. CONCLUSIONS: Our results are a proof of principle that microneurography could be used as a useful tool to assist the development of more effective hand prostheses.

Different nerve ultrasound patterns in charcot-marie-tooth types and hereditary neuropathy with liability to pressure palsies.

INTRODUCTION: Nerve ultrasound in Charcot-Marie-Tooth (CMT) disease has focused mostly on the upper limbs. We performed an evaluation of a large cohort of CMT patients in which we sonographically characterized nerve abnormalities in different disease types, ages, and nerves. METHODS: Seventy patients affected by different CMT types and hereditary neuropathy with liability to pressure palsies (HNPP) were evaluated, assessing median, ulnar, fibular, tibial, and sural nerves bilaterally. Data were correlated with age. RESULTS: Nerve dimensions were correlated with CMT type, age, and nerve site. Nerves were larger in demyelinating than in axonal neuropathies. Nerve involvement was symmetric. DISCUSSION: CMT1 patients had larger nerves than did patients with other CMT types. Patients with HNPP showed enlargement at entrapment sites. Our study confirms the general symmetry of ultrasound nerve patterns in CMT. When compared with ultrasound studies of nerves of the upper limbs, evaluation of the lower limbs did not provide additional information. Muscle Nerve 57: E18-E23, 2018.

Transcranial direct current stimulation generates a transient increase of small-world in brain connectivity: an EEG graph theoretical analysis.

Transcranial direct current stimulation (tDCS) is a non-invasive technique able to modulate cortical excitability in a polarity-dependent way. At present, only few studies investigated the effects of tDCS on the modulation of functional connectivity between remote cortical areas. The aim of this study was to investigate-through graph theory analysis-how bipolar tDCS modulate cortical networks high-density EEG recordings were acquired before and after bipolar cathodal, anodal and sham tDCS involving the primary motor and pre-motor cortices of the dominant hemispherein 14 healthy subjects. Results showed that, after bipolar anodal tDCS stimulation, brain networks presented a less evident "small world" organization with a global tendency to be more random in its functional connections with respect to prestimulus condition in both hemispheres. Results suggest that tDCS globally modulates the cortical connectivity of the brain, modifying the underlying functional organization of the stimulated networks, which might be related to changes in synaptic efficiency of the motor network and related brain areas. This study demonstrated that graph analysis approach to EEG recordings is able to intercept changes in cortical functions mediated by bipolar anodal tDCS mainly involving the dominant M1 and related motor areas. Concluding, tDCS could be an useful technique to help understanding brain rhythms and their topographic functional organization and specificity.

Potential Eye Drop Based on a Calix[4]arene Nanoassembly for Curcumin Delivery: Enhanced Drug Solubility, Stability, and Anti-Inflammatory Effect.

Curcumin is an Indian spice with a wide spectrum of biological and pharmacological activities but poor aqueous solubility, rapid degradation, and low bioavailability that affect medical benefits. To overcome these limits in ophthalmic application, curcumin was entrapped in a polycationic calix[4]arene-based nanoaggregate by a simple and reproducible method. The calix[4]arene-curcumin supramolecular assembly (Calix-Cur) appeared as a clear colloidal solution consisting in micellar nanoaggregates with size, polydispersity index, surface potential, and drug loading percentage meeting the requirements for an ocular drug delivery system. The encapsulation in the calix[4]arene nanoassembly markedly enhanced the solubility, reduced the degradation, and improved the anti-inflammatory effects of curcumin compared to free curcumin in both in vitro and in vivo experiments. Calix-Cur did not compromise the viability of J774A.1 macrophages and suppressed pro-inflammatory marker expression in J774A.1 macrophages subjected to LPS-induced oxidative stress. Histological and immunohistochemical analyses showed that Calix-Cur reduced signs of inflammation in a rat model of LPS-induced uveitis when topically administrated in the eyes. Overall, the results supported the calix[4]arene nanoassembly as a promising nanocarrier for delivering curcumin to anterior ocular tissues.

Prognostic Value of EEG Microstates in Acute Stroke.

Given the importance of neuronal plasticity in recovery from a stroke and the huge variability of recovery abilities in patients, we investigated neuronal activity in the acute phase to enhance information about the prognosis of recovery in the stabilized phase. We investigated the microstates in 47 patients who suffered a first-ever mono-lesional ischemic stroke in the middle cerebral artery territory and in 20 healthy control volunteers. Electroencephalographic (EEG) activity at rest with eyes closed was acquired between 2 and 10 days (T0) after ischemic attack. Objective criteria allowed for the selection of an optimal number of microstates. Clinical condition was quantified by the National Institute of Health Stroke Scale (NIHSS) both in acute (T0) and stabilized (T1, 5.4 ± 1.7 months) phases and Effective Recovery (ER) was calculated as (NIHSS(T1)-NIHSS(T0))/NIHSS(T0). The microstates A, B, C and D emerged as the most stable. In patients with a left lesion inducing a language impairment, microstate C topography differed from controls. Microstate D topography was different in patients with a right lesion inducing neglect symptoms. In patients, the C vs D microstate duration differed after both a left and a right lesion with respect to controls (C lower than D in left and D lower than C in right lesion). A preserved microstate B in acute phase correlated with a better effective recovery. A regression model indicated that the microstate B duration explained the 11% of ER variance. This first ever study of EEG microstates in acute stroke opens an interesting path to identify neuronal impairments with prognostic relevance, to develop enriched compensatory treatments to drive a better individual recovery.

Secondary posterior interosseous nerve lesions associated with humeral fractures.

INTRODUCTION: Radial nerve lesions associated with humeral shaft fractures are the most common traumatic nerve lesions observed with long bone fractures. Secondary indirect posterior interosseous nerve (PIN) lesions can be associated with traumatic radial nerve palsy. The aim of this study was to identify cases of traumatic double-site radial nerve involvement through ultrasound (US). METHODS: Patients with traumatic radial nerve lesions referred to our laboratory from January 2010 to January 2014 were evaluated. RESULTS: Of the 35 patients, 18 had US evidence of a radial nerve lesion at the fracture site associated with secondary PIN involvement at the arcade of Frohse. CONCLUSIONS: Multiple-site nerve lesions are difficult to demonstrate through electrodiagnostic tests. In our case series, half of the patients with traumatic radial nerve damage had US evidence of PIN injury. Prospective studies with follow-up are needed to determine the clinical and prognostic relevance of this finding and the best therapeutic approach.