Successful Desensitization to Sorafenib and Imatinib-A Report of Two Cases and a Literature Review.

BACKGROUND: Drug desensitization allows for safe administration of a drug to a patient with a previous hypersensitivity reaction. Successful desensitization protocols have been described for different medications, including protocols for oncology patients. Few cases of desensitization to sorafenib and imatinib have been described in the literature so far. OBJECTIVE: The objective of this paper is to describe the process of the sorafenib and imatinib drug hypersensitivity diagnosis and desensitization process in two patients. METHODS: Two oncology patients who experienced non-immediate hypersensitivity reactions to sorafenib and imatinib underwent desensitization to these drugs. We designed a protocol for the first patient and used a modified protocol from the literature for the second patient. RESULTS: By using a slow desensitization technique and gradual tapering of corticosteroids and antihistamines, both patients reached the target dose of the incriminated drug. CONCLUSIONS: Desensitization to sorafenib and imatinib can be an effective therapeutic option in patients with hypersensitivity to those medications, without alternative treatment options.

Asthma Inflammatory Phenotypes: How Can We Distinguish Them?

BACKGROUND AND OBJECTIVES: induced sputum is used to assess different inflammatory phenotypes in asthma, but is not used routinely. We aimed to determine the proportion of inflammatory asthma phenotypes based on induced sputum, to find biomarkers that can discriminate between phenotypes, and to evaluate biomarkers in patients with and without biological therapy in different inflammatory asthma phenotypes. MATERIALS AND METHODS: this cross-sectional study investigated clinical characteristics, asthma control tests, skin prick test, impulse oscillometry (IOS), spirometry, induced sputum, biomarkers (IgE, eosinophils, fractional exhaled nitric oxide (FeNO), serum periostin, IL-5, IL-6, IL-8, IL-17A, IL-33) in 80 asthmatics. A total of 17/80 patients were treated with biologics (10 with omalizumab, 7 with benralizumab). RESULTS: a total of 31% of patients had eosinophilic asthma (EA), 30% had mixed granulocytic asthma (MGA), 24% had paucigranulocytic asthma (PGA), and 15% had neutrophilic asthma (NA). The difference was found in blood eosinophils (p = 0.002), the highest observed in EA. The cut-off ≥ 240/µL eosinophils, with 64% sensitivity and 72.7% specificity, identified EA (AUC = 0.743, p = 0.001). A higher IL-8 level was associated with NA (p = 0.025). In 63 non-biologic asthma group, eosinophils were higher in EA than in NA, MGA, and PGA (p = 0.012, p = 0.028, and p = 0.049, respectively). A higher IL-17A was associated with EA without biologics (p = 0.004). A significantly higher IL-5 was found in EA treated with biologics, in comparison with EA without biologics (p = 0.043). The number of leucocytes and neutrophils was higher in MGA without biologics (p = 0.049, p = 0.019), while IL-5, IL-6, and IL-8 levels were higher in MGA treated with biologics (p = 0.012, p = 0.032, p = 0.038, respectively). CONCLUSIONS: EA and MGA were the most prevalent asthma phenotypes. Blood eosinophils can identify EA, both in patients with and without biologics. Apart from the clinical profile, a broad spectrum of biomarkers for assessing inflammatory phenotypes is necessary for an adequate therapy approach to patients with asthma.

Autoimmune/inflammatory syndrome induced by adjuvants in a woman with Hashimoto thyroiditis and familial autoimmunity-a case report and literature review.

Introduction: Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) consists of a wide spectrum of symptoms and immunological features that are believed to develop in predisposed individuals after exposure to an adjuvant, including a silicone breast implant (SBI). Different autoimmune diseases (AIDs) have been associated with ASIA, but ASIA development after SBI in women with Hashimoto thyroiditis (HT) and familial autoimmunity has rarely been described. Case report: A 37-year-old woman presented in 2019 with arthralgia, sicca symptoms, fatigue, + antinuclear antibody (ANA), + anti SSA, and + anticardiolipin Immunoglobulin G (IgG) antibodies. She was diagnosed with HT and vitamin D deficiency in 2012. The familial autoimmunity was present: the patient's mother had been diagnosed with systemic lupus erythematosus and secondary Sjogren's syndrome and her grandmother with cutaneous lupus and pernicious anemia. In 2017, the patient had a cosmetic SBI procedure that was complicated by repeated right breast capsulitis. After 2 years of irregular visits due to COVID-19, she presented with + ANA, + anticentromere antibodies both in sera and seroma, sicca syndrome, arthralgias, twinkling in extremities, abnormal capillaroscopic findings, and reduced diffusing capacity of the lungs for carbon monoxide. She was diagnosed with ASIA, and antimalarial and corticosteroid therapy were introduced. Conclusion: In patients with HT and familial autoimmunity, SBI should be carefully considered due to the possibility of ASIA development. Hashimoto thyroiditis, familial autoimmunity, and ASIA seem to be interconnected in the complex mosaic of autoimmunity in predisposed individuals.

Neurophysiology of epidurally evoked spinal cord reflexes in clinically motor-complete posttraumatic spinal cord injury.

Increased use of epidural Spinal Cord Stimulation (eSCS) for the rehabilitation of spinal cord injury (SCI) has highlighted the need for a greater understanding of the properties of reflex circuits in the isolated spinal cord, particularly in response to repetitive stimulation. Here, we investigate the frequency-dependence of modulation of short- and long-latency EMG responses of lower limb muscles in patients with SCI at rest. Single stimuli could evoke short-latency responses as well as long-latency (likely polysynaptic) responses. The short-latency component was enhanced at low frequencies and declined at higher rates. In all muscles, the effects of eSCS were more complex if polysynaptic activity was elicited, making the motor output become an active process expressed either as suppression, tonic or rhythmical activity. The polysynaptic activity threshold is not constant and might vary with different stimulation frequencies, which speaks for its temporal dependency. Polysynaptic components can be observed as direct responses, neuromodulation of monosynaptic responses or driving the muscle activity by themselves, depending on the frequency level. We suggest that the presence of polysynaptic activity could be a potential predictor for appropriate stimulation conditions. This work studies the complex behaviour of spinal circuits deprived of voluntary motor control from the brain and in the absence of any other inputs. This is done by describing the monosynaptic responses, polysynaptic activity, and its interaction through its input-output interaction with sustain stimulation that, unlike single stimuli used to study the reflex pathway, can strongly influence the interneuron circuitry and reveal a broader spectrum of connectivity.

Biomarkers of disease activity in patients with chronic spontaneous urticaria.

INTRODUCTION: Previous studies have examined biomarkers of coagulation, inflammation and immunity in chronic spontaneous urticaria (CSU), but no recommended biomarkers for disease activity have been established yet. AIM: To find the relationship between certain laboratory parameters and disease activity in patients with CSU. MATERIAL AND METHODS: Serum concentrations of D-dimer, C-reactive protein (CRP), C3, C4, and prothrombin time (PT), activated partial thromboplastin time (aPTT) values were measured in 44 CSU patients and compared with 33 healthy controls. Correlation between biomarkers and urticaria activity score during 7 consecutive days (UAS7) was calculated. RESULTS: Our study included 44 CSU patients (38 females and 6 males), mean age of 50.4 years and the average disease duration of 3.1 years. Based on UAS7, 23 (52.3%) CSU patients had mild urticaria, 8 (18.2%) well-controlled, 7 (15.9%) moderate and 6 (13.6%) severe urticaria. Fourteen (31.8%) patients had elevated CRP, 21 (47.7%) had elevated D-dimer and 14 (13.6%) CSU patients had elevated C4 levels. Patients with CSU had statistically significant elevated D-dimer, CRP and PT as compared with controls (p = 0.007, p = 0.005 and p = 0.029, respectively). There was no correlation between PT, aPTT, D-dimer, CRP, C3 and disease activity. Statistically significant differences in C4 levels between patients with severe and well-controlled, mild, moderate urticaria were determined (p = 0.003). CONCLUSIONS: CRP, D-dimer, and PT may be considered as biomarkers for distinguishing patients with CSU from controls. The C4 levels correlate with disease activity and may be useful as a potential biomarker of disease activity.

Spinal cord injuries, human neuropathology and neurophysiology.

A correlative approach to human spinal cord injuries (SCI) through the combination of neuropathology and neurophysiology provides a much better understanding of the condition than with either alone. Among the benefits so derived is the wide range of interventions applicable to the restorative neurology (RN) of SCI so that the neurological status of the SCI patient is thereby much improved. The neurophysiological and neuropathological elements underlying these advances are described.

Photodestruction of Diatomic Molecular Ions: Laboratory and Astrophysical Application.

In this work, the processes of photodissociation of some diatomic molecular ions are investigated. The partial photodissociation cross-sections for the individual rovibrational states of the diatomic molecular ions, which involves alkali metals, as well as corresponding data on molecular species and molecular state characterizations, are calculated. Also, the average cross-section and the corresponding spectral absorption rate coefficients for those small molecules are presented in tabulated form as a function of wavelengths and temperatures. The presented results can be of interest for laboratory plasmas as well as for the research of chemistry of different stellar objects with various astrophysical plasmas.

Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017).

Cell therapy has been shown to be a key clinical therapeutic option for central nervous system diseases or damage. Standardization of clinical cell therapy procedures is an important task for professional associations devoted to cell therapy. The Chinese Branch of the International Association of Neurorestoratology (IANR) completed the first set of guidelines governing the clinical application of neurorestoration in 2011. The IANR and the Chinese Association of Neurorestoratology (CANR) collaborated to propose the current version "Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)". The IANR council board members and CANR committee members approved this proposal on September 1, 2016, and recommend it to clinical practitioners of cellular therapy. These guidelines include items of cell type nomenclature, cell quality control, minimal suggested cell doses, patient-informed consent, indications for undergoing cell therapy, contraindications for undergoing cell therapy, documentation of procedure and therapy, safety evaluation, efficacy evaluation, policy of repeated treatments, do not charge patients for unproven therapies, basic principles of cell therapy, and publishing responsibility.

Motor Control of Human Spinal Cord Disconnected from the Brain and Under External Movement.

Motor control after spinal cord injury is strongly depending on residual ascending and descending pathways across the lesion. The individually altered neurophysiology is in general based on still intact sublesional control loops with afferent sensory inputs linked via interneuron networks to efferent motor outputs. Partial or total loss of translesional control inputs reduces and alters the ability to perform voluntary movements and results in motor incomplete (residual voluntary control of movement functions) or motor complete (no residual voluntary control) spinal cord injury classification. Of particular importance are intact functionally silent neural structures with residual brain influence but reduced state of excitability that inhibits execution of voluntary movements. The condition is described by the term discomplete spinal cord injury. There are strong evidences that artificial afferent input, e.g., by epidural or noninvasive electrical stimulation of the lumbar posterior roots, can elevate the state of excitability and thus re-enable or augment voluntary movement functions. This modality can serve as a powerful assessment technique for monitoring details of the residual function profile after spinal cord injury, as a therapeutic tool for support of restoration of movement programs and as a neuroprosthesis component augmenting and restoring movement functions, per se or in synergy with classical neuromuscular or muscular electrical stimulation.

Epidural and transcutaneous spinal electrical stimulation for restoration of movement after incomplete and complete spinal cord injury.

PURPOSE OF REVIEW: The Purpose of this review is to outline and explain the therapeutic use of electrical spinal cord stimulation (SCS) for modification of spinal motor output. Central functional stimulation provides afferent input to posterior root neurons and is applied to improve volitional movements, posture and their endurance, control spasticity, and improve bladder function or perfusion in the lower limbs. Clinical accomplishments strongly depend on each individual's physiological state and specific methodical adaptation to that physiological state. RECENT FINDINGS: Effectiveness of this neuromodulory technique for changing motor control after spinal cord injury (SCI) continues to be explored along with the underlying mechanisms of its effect in people with complete and incomplete spinal cord injuries. There are extensive studies of tonic and rhythmical activity elicited from the lumbar cord as well as data demonstrating augmentation of residual volitional activity. Recent studies have focused on verifying if and how SCS can modify features of neurocontrol in ambulatory spinal cord patients. SUMMARY: In this review, we emphasize recent publications of research revealing that SCS can substitute for the reduced brain drive for control of excitability in people with SCI. Artificially replacing diminished or lost brain control over the spinal cord has limitations. A fundamental requirement for successful SCS application is analysis of each individual's residual postinjury neural function. This will allow a better understanding of the physiological interactions between SCS and spinal cord motor control below injury and provide criteria for its application. Finally, the publication of both successful and failed applications of SCS will be crucial for gaining future progress.

Neurocontrol of Movement in Humans With Spinal Cord Injury.

In this review of neurocontrol of movement after spinal cord injury, we discuss neurophysiological evidences of conducting and processing mechanisms of the spinal cord. We illustrate that external afferent inputs to the spinal cord below the level of the lesion can modify, initiate, and maintain execution of movement in absence or partial presence of brain motor control after chronic spinal cord injury. We review significant differences between spinal reflex activity elicited by single and repetitive stimulation. The spinal cord can respond with sensitization, habituation, and dis-habituation to regular repetitive stimulation. Therefore, repetitive spinal cord reflex activity can contribute to the functional configuration of the spinal network. Moreover, testing spinal reflex activity in individuals with motor complete spinal cord injury provided evidences for subclinical residual brain influence, suggesting the existence of axons traversing the injury site and influencing the activities below the level of lesion. Thus, there are two motor control models of chronic spinal cord injury in humans: "discomplete" and "reduced and altered volitional motor control." We outline accomplishments in modification and initiation of altered neurocontrol in chronic spinal cord injury people with epidural and functional electrical stimulation. By nonpatterned electrical stimulation of lumbar posterior roots, it is possible to evoke bilateral extension as well as rhythmic motor outputs. Epidural stimulation during treadmill stepping shows increased and/or modified motor activity. Finally, volitional efforts can alter epidurally induced rhythmic activities in incomplete spinal cord injury. Overall, we highlight that upper motor neuron paralysis does not entail complete absence of connectivity between cortex, brain stem, and spinal motor cells, but there can be altered anatomy and corresponding neurophysiological characteristics. With specific input to the spinal cord below the level of the lesion, the clinical status of upper motor neuron paralysis without structural modification can be modified, and movements can be initiated. Thus, external afferent input can partially replace brain control.

Outline of restorative neurology: definition, clinical practice, assessment, intervention.

Rather than focusing on the deficits and lost function caused by upper motor neuron lesions or disorders, it is more advantageous to elucidate, in each individual, the specific neural functions that remain available, and then, to build upon them by designing a treatment protocol to optimize their effectiveness and thus improve recovery. The practice of Restorative Neurology is based on detailed assessment of the individual patient, the use of neurophysiological methods to elucidate and characterize subclinical function and the application of interventions that modify neural activity to improve clinical function.

Stimulation of the human lumbar spinal cord with implanted and surface electrodes: a computer simulation study.

Human lumbar spinal cord networks controlling stepping and standing can be activated through posterior root stimulation using implanted electrodes. A new stimulation method utilizing surface electrodes has been shown to excite lumbar posterior root fibers similarly as with implants, an unexpected finding considering the distance to these target neurons. In the present study we apply computer modeling to compare the depolarization of posterior root fibers by both stimulation techniques. We further examine the potential for additional direct activation of motoneurons within the anterior roots. Using an implant, action potentials are initiated in the posterior root fibers at their entry into the spinal cord or along the longitudinal portions of the fiber trajectories, depending on the cathode position. For transcutaneous stimulation low threshold sites of the same fibers are identified at their exits from the spinal canal in addition to their spinal cord entries. In these exit regions anterior root fibers can also be activated. The simulation results provide a biophysical explanation for the electrophysiological findings of lower limb muscle responses induced by posterior root stimulation. Efficient excitation of afferent spinal cord structures with a simple noninvasive method can become a promising modality in the rehabilitation of people with motor disorders.

Clinical practice of functional electrical stimulation: from "Yesterday" to "Today".

Functional electrical stimulation (FES) is an accepted treatment method for paresis or paralysis after spinal cord and head injury as well as stroke and other neurological upper motor neuron disorders. At the beginning, FES worked like an electrophysiological brace for the correction of drop foot of patients after a stroke. When analyzing early accomplishments, it becomes evident that FES was influenced rather by technological and biomedical engineering development than by contemporary knowledge on neurocontrol of movement in individuals with upper motor neuron paralysis. Nevertheless, with better understanding of pathophysiology of spasticity and neurocontrol of impaired movement, FES advanced from an electrophysiological brace to a treatment modality for the improvement of muscle control, neuroaugmentation of residual movements, and supportive procedure for "spontaneous recovery" of motor control. In the present article we shall illustrate barriers which delayed FES to be applied in clinical practice of neuron rehabilitation from "Yesterday" to "Today." We shall discuss the importance to apply FES early after the onset of neurological conditions to prevent disuse of noninjured portions of the CNS. Moreover, FES can play a significant role in the supporting processes of neuroplasticity in the subacute phase of upper motor neuron dysfunction. Therefore, the electrophysiological brace of "Yesterday" provides "Today" a correction of missing neuromuscular function. At the same time, it is an active external device for the correction of motor deficits interacting with the somatosensory-motor integration. Thus, "Yesterday" and "Today" of the same technological approach can be very different, thanks to a different understanding and assessment of "external" and "internal" components of human motor control.

Modification of reflex responses to lumbar posterior root stimulation by motor tasks in healthy subjects.

Dynamic task-dependent regulation of reflexes controlled by the central nervous system plays an integral part in neurocontrol of locomotion. Such modifications of sensory-motor transmission can be studied by conditioning a test reflex with specific motor tasks. To elicit short-latency test reflexes, we applied a novel transcutaneous spinal cord stimulation technique that depolarizes large-diameter posterior root afferents. These responses, termed posterior root-muscle (PRM) reflexes, are equivalent to the monosynaptic Hoffmann (H)-reflex but can be evoked in several muscles simultaneously. We elicited PRM reflexes in quadriceps, hamstrings, tibialis anterior, and triceps surae in subjects with intact nervous system. During three different conditioning-test paradigms in a standing position, that is, volitional unilateral single- and multi-joint lower limb movements and leaning backward/forward, we recorded characteristic movement-induced modulations of PRM reflexes in the thigh and leg muscle groups. We could thus demonstrate that monosynaptic PRM reflexes in functional extensor and flexor muscles of the thigh and leg can be elicited in upright standing subjects and can be modulated during the execution of postural maneuvers. The significance is that transcutaneous posterior root stimulation allows extending H-reflex studies of a single muscle to the assessment of synaptic transmission of two-neuron reflex arcs at multiple segmental levels simultaneously.

Posterior root-muscle reflexes elicited by transcutaneous stimulation of the human lumbosacral cord.

Continuous epidural stimulation of lumbar posterior root afferents can modify the activity of lumbar cord networks and motoneurons, resulting in suppression of spasticity or elicitation of locomotor-like movements in spinal cord-injured people. The aim of the present study was to demonstrate that posterior root afferents can also be depolarized by transcutaneous stimulation with moderate stimulus intensities. In healthy subjects, single stimuli applied through surface electrodes placed over the T11-T12 vertebrae with a mean intensity of 28.6 V elicited simultaneous, bilateral monosynaptic reflexes in quadriceps, hamstrings, tibialis anterior, and triceps surae by depolarization of lumbosacral posterior root fibers. The nature of these posterior root-muscle reflexes was demonstrated by the duration of the refractory period, and by modifying the responses with vibration and active and passive movements. Stimulation over the L4-L5 vertebrae selectively depolarized posterior root fibers or additionally activated anterior root fibers within the cauda equina depending on stimulus intensity. Transcutaneous posterior root stimulation with single pulses allows neurophysiological studies of state- and task-dependent modulations of monosynaptic reflexes at multiple segmental levels. Continuous transcutaneous posterior root stimulation represents a novel, non-invasive, neuromodulative approach for individuals with different neurological disorders.

Motor control in the human spinal cord.

Features of the human spinal cord motor control are described using two spinal cord injury models: (i) the spinal cord completely separated from brain motor structures by accidental injury; (ii) the spinal cord receiving reduced and altered supraspinal input due to an incomplete lesion. Systematic studies using surface electrode polyelectromyography were carried out to assess skeletal muscle reflex responses to single and repetitve stimulation in a large number of subjects. In complete spinal cord injured subjects the functional integrity of three different neuronal circuits below the lesion level is demonstrated: first, simple mono- and oligosynaptic reflex arcs and polysynaptic pathways; second, propriospinal interneuron system with their cell in the gray matter and the axons in the white matter of the spinal cord conducting activity between different spinal cord segments; and third, internuncial gray matter neurons with short axons and dense neuron contact within the spinal gray matter. All of these three systems participate continuously in the generation of spinal cord reflex output activating muscles. The integration of these systems and their relative degree of excitation and set-up produces characteristic functions of motor control. In incomplete spinal cord injured patients, the implementation of brain motor control depends on the profile of residual brain descending input and its integration with the functional neuronal circuits below the lesion. Locomotor patterns result from the establishment of a new structural relationship between brain and spinal cord. The functions of this new structural relationship are expressed as an alternative, but characteristic and consistent neurocontrol. The more we know about how the brain governs spinal cord networks, the better we can describe human motor control. On the other hand such knowledge is essential for the restoration of residual functions and for the construction of new cord circuitry to expand the functions of the injured spinal cord.

Frequency-dependent selection of alternative spinal pathways with common periodic sensory input.

Electrical stimulation of the lumbar cord at distinct frequency ranges has been shown to evoke either rhythmical, step-like movements (25-50 Hz) or a sustained extension (5-15 Hz) of the paralysed lower limbs in complete spinal cord injured subjects. Frequency-dependent activation of previously "silent" spinal pathways was suggested to contribute to the differential responsiveness to distinct neuronal "codes" and the modifications in the electromyographic recordings during the actual implementation of the evoked motor tasks. In the present study we examine this suggestion by means of a simplified biology-based neuronal network. Involving two basic mechanisms, temporal summation of synaptic input and presynaptic inhibition, the model exhibits several patterns of mono- and/or oligo-synaptic motor output in response to different interstimulus intervals. It thus reproduces fundamental input-output features of the lumbar cord isolated from the brain. The results confirm frequency-dependent spinal pathway selection as a simple mechanism which enables the cord to respond to distinct neuronal codes with different motor behaviours and to control the actual performance of the latter.

Clinical elements for the neuromuscular stimulation and functional electrical stimulation protocols in the practice of neurorehabilitation.

The physicians and their multidisciplinary teams involved in the clinical practice of neurological rehabilitation have more and more opportunities to apply neuromuscular stimulation (NMS) and functional electrical stimulation (FES) of peripheral nerves as a part of their daily practice. In this article, we outline clinical protocols of NMS and FES in the following clinical conditions of upper motor neuron dysfunction: to prevent consequences of disuse of the neuromuscular system of the upper motor neuron, to facilitate recovery processes of impaired upper motor neuron functions due to acute and/or subacute neurological conditions, to maintain or enhance the trophic state of the muscle, to modify altered control of muscle tone, to modify altered patterns of automatic and volitional functional movements, to enhance functional movement of the single joint muscle group within intact functional multijoint movement, and to modify altered neurocontrol of posture, locomotion, and skillful movements. We emphasize the importance of understanding the motor control alteration while developing clinical protocols and defining the goals. It is very important to be aware that similar clinical findings and due to the same cause can have different features of residual motor control, and therefore potentials for recovery or modification can be very different.

Recent concepts in the pathophysiology and evaluation of spasticity / Conceptos recientes en la evaluación y fisiopatología de la espasticidad

La espasticidad es aún un desafío a médicos y científicos. Revisamos aquí los conceptos modernos acerca del compromiso de las fibras aferentes la II, III y IV así como también de aquellas que participan en la inhibición presináptica, la modulación de las células de Renshaw e hiperexcitabilidad de las motoneuronas alfa y gama que tienen que ver con este problema médico. Los estudios neurofisiológicos más comunes para evalaur la espasticidad humana son brevemente discutidos