Multidisciplinary Care of Patients with Facial Palsy: Treatment of 1220 Patients in a German Facial Nerve Center

To determine treatment and outcome in a tertiary multidisciplinary facial nerve center, a retrospective observational study was performed of all patients referred between 2007 and 2018. Facial grading with the Stennert index, the Facial Clinimetric Evaluation (FaCE) scale, and the Facial Disability Index (FDI) were used for outcome evaluation; 1220 patients (58.4% female, median age: 50 years; chronic palsy: 42.8%) were included. Patients with acute and chronic facial palsy were treated in the center for a median of 3.6 months and 10.8 months, respectively. Dominant treatment in the acute phase was glucocorticoids ± acyclovir (47.2%), followed by a significant improvement of all outcome measures (p < 0.001). Facial EMG biofeedback training (21.3%) and botulinum toxin injections (11%) dominated the treatment in the chronic phase, all leading to highly significant improvements according to facial grading, FDI, and FaCE (p < 0.001). Upper eyelid weight (3.8%) and hypoglossal–facial-nerve jump suture (2.5%) were the leading surgical methods, followed by improvement of facial motor function (p < 0.001) and facial-specific quality of life (FDI, FaCE; p < 0.05). A standardized multidisciplinary team approach in a facial nerve center leads to improved facial and emotional function in patients with acute or chronic facial palsy.

The Colombian Strain of Trypanosoma cruzi Induces a Proinflammatory Profile, Neuronal Death, and Collagen Deposition in the Intestine of C57BL/6 Mice Both during the Acute and Early Chronic Phase

The objective of this study was to evaluate the histopathological changes caused by infection with the Colombian strain of Trypanosoma cruzi (T. cruzi) in the acute and chronic experimental phases. C57Bl/6 mice were infected with 1000 trypomastigote forms of the Colombian strain of T. cruzi. After 30 days (acute phase) and 90 days (early chronic phase) of infection, the animals were euthanized, and the colon was collected and divided into two parts: proximal and distal. The distal portion was used for histopathological analysis, whereas the proximal portion was used for quantification of pro- and anti-inflammatory cytokines. In addition, the weight of the animals and parasitemia were assessed. The infection induced gradual weight loss in the animals. In addition, the infection induced an increase in interferon gamma (IFNγ) and tumor necrosis factor-alpha (TNF-α) in the intestine in the acute phase, in which this increase continued until the early chronic phase. The same was observed in relation to the presence of intestinal inflammatory infiltrates. In relation to interleukin (IL)-10, there was an increase only in the early chronic phase. The Colombian strain infection was also able to induce neuronal loss in the myenteric plexus and deposition of the collagen fibers during the acute phase. The Colombian strain of T. cruzi is capable of causing histopathological changes in the intestine of infected mice, especially in inducing neuronal destructions. Thus, this strain can also be used to study the intestinal form of Chagas disease in experimental models.

Role of Palatine Tonsil and Epipharyngeal Lymphoid Tissue in the Development of Glomerular Active Lesions (Glomerular vasculitis) in Immunoglobulin A Nephropathy

Hematuria is an essential symptom of immunoglobulin A nephropathy (IgAN). Although the etiology of hematuria in IgAN has not been fully elucidated, it is thought that the rupture of the glomerular basement membranes caused by intra-capillary leukocyte influx, so-called glomerular vasculitis, is the pathological condition responsible for severe hematuria. Glomerular vasculitis are active lesions that exist in the glomeruli of acute phase IgAN and it is important because it is suspected to make the transition to segmental glomerular sclerosis (SGS) as a repair scar lesion in the chronic phase, and the progression of SGS would eventually lead to glomerular obsolescence. Worsening of hematuria concomitant with acute pharyngitis is common in patients with IgAN; therefore, elucidating the relationship between the immune system of Waldeyer’s ring, including the palatine tonsil and epipharyngeal lymphoid tissue, and the glomerular vasculitis may lead to understanding the nature of IgAN. The epipharynx is an immunologically activated site even under normal conditions, and enhanced activation of innate immunity is likely to occur in response to airborne infection. Hyperactivation of innate immunity via upregulation of Toll-like receptors in the interfollicular area of the palatine tonsil and epipharyngeal lymphoid tissue, followed by enhanced fractalkine/CX3CR1 interactions, appears to play an important role in the development of glomerular vasculitis in IgAN. As latent but significant epipharyngitis is present in most patients with IgAN, it is plausible that acute upper respiratory infection may contribute as a trigger for the innate epipharyngeal immune system, which is already upregulated in a chronically inflamed environment. Given that epipharyngitis and its effects on IgAN are not fully understood, we propose that the so-called “epipharynx–kidney axis” may provide an important focus for future research.

Comparative Gene Expression Analysis Reveals Similarities and Differences of Chronic Myeloid Leukemia Phases

Chronic myeloid leukemia (CML) is a slowly progressing blood cancer that primarily affects elderly people. Without successful treatment, CML progressively develops from the chronic phase through the accelerated phase to the blast crisis, and ultimately to death. Nowadays, the availability of targeted tyrosine kinase inhibitor (TKI) therapies has led to long-term disease control for the vast majority of patients. Nevertheless, there are still patients that do not respond well enough to TKI therapies and available targeted therapies are also less efficient for patients in accelerated phase or blast crises. Thus, a more detailed characterization of molecular alterations that distinguish the different CML phases is still very important. We performed an in-depth bioinformatics analysis of publicly available gene expression profiles of the three CML phases. Pairwise comparisons revealed many differentially expressed genes that formed a characteristic gene expression signature, which clearly distinguished the three CML phases. Signaling pathway expression patterns were very similar between the three phases but differed strongly in the number of affected genes, which increased with the phase. Still, significant alterations of MAPK, VEGF, PI3K-Akt, adherens junction and cytokine receptor interaction signaling distinguished specific phases. Our study also suggests that one can consider the phase-wise CML development as a three rather than a two-step process. This is in accordance with the phase-specific expression behavior of 24 potential major regulators that we predicted by a network-based approach. Several of these genes are known to be involved in the accumulation of additional mutations, alterations of immune responses, deregulation of signaling pathways or may have an impact on treatment response and survival. Importantly, some of these genes have already been reported in relation to CML (e.g., AURKB, AZU1, HLA-B, HLA-DMB, PF4) and others have been found to play important roles in different leukemias (e.g., CDCA3, RPL18A, PRG3, TLX3). In addition, increased expression of BCL2 in the accelerated and blast phase indicates that venetoclax could be a potential treatment option. Moreover, a characteristic signaling pathway signature with increased expression of cytokine and ECM receptor interaction pathway genes distinguished imatinib-resistant patients from each individual CML phase. Overall, our comparative analysis contributes to an in-depth molecular characterization of similarities and differences of the CML phases and provides hints for the identification of patients that may not profit from an imatinib therapy, which could support the development of additional treatment strategies.

Prolonged release of VEGF and Ang1 from intralesionally implanted hydrogel promotes perilesional vascularization and functional recovery after experimental ischemic stroke

Injectable hydrogels can generate and support pro-repair environments in injured tissue. Here we used a slow-releasing drug carrying in situ-forming hydrogel to promote post-stroke recovery in a rat model. Release kinetics were measured in vitro and in vivo with MRI, using gadolinium-labeled albumin (Galbumin), which demonstrated prolonged release over multiple weeks. Subsequently, this hydrogel was used for long-term delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) (Gel VEGF + Ang1, n = 14), in a photothrombotically induced cortical stroke lesion in rats. Control stroke animals were intralesionally injected with saline (Saline, n = 10), non-loaded gel (Gel, n = 10), or a single bolus of VEGF + Ang1 in saline (Saline VEGF + Ang1, n = 10). MRI was executed to guide hydrogel injection. Functional recovery was assessed with sensorimotor function tests, while tissue status and vascularization were monitored by serial in vivo MRI. Significant recovery from sensorimotor deficits from day 28 onwards was only measured in the Gel VEGF + Ang1 group. This was accompanied by significantly increased vascularization in the perilesional cortex. Histology confirmed (re)vascularization and neuronal sparing in perilesional areas. In conclusion, intralesional injection of in situ-forming hydrogel loaded with pro-angiogenic factors can support prolonged brain tissue regeneration and promote functional recovery in the chronic phase post-stroke.

Tyrosine kinase inhibitor nilotinib induced palmoplantar erythrodysesthesia: A rare case

Introduction Nilotinib is a second generation Tyrosine Kinase inhibitor (TKI) used in the treatment of Chronic Myeloid Leukemia (CML). The development of tyrosine kinase inhibitors has transformed chronic phase chronic myeloid leukemia from a disease with a poor prognosis to a treatable chronic disease. Long-term treatment with tyrosine kinase inhibitors means that patients must be clinically managed and monitored for years. While under Nilotinib tretament, the development of palmoplantar erythrodyesthesia is a very rare condition compared to other oncological drugs. Case report A 66-year-old male patient, who was diagnosed with chronic phase CML in 2019 had been placed under imatinib treatment . He had major molecular response loss in 2021, and was started on second generation TKI nilotinib 2 × 400mg/day, considering his comorbidities. We present a case of a 66-year-old patient with CML who developed palmoplantar erythrodysesthesia on the 21st day starting nilotinib treatment. Conclusion It is important to manage the side effects that develop in long-term treatments. Adverse events can have a negative impact on patient compliance and quality of life and lead to poor clinical outcomes Our case is the first to develop PPE after beginning nilotinib use. We present this phenomenon to raise awareness and ignite a review of management strategies.In this case, we wanted to emphasize the importance of managing side effects.

Safety and Long-term Improvement of Mesenchymal Stromal Cell Infusion in Critically COVID-19 Patients: A Randomized Clinical Trial.

Background: COVID-19 is a multisystem disease that presents acute and persistent symptoms, the PostAcute Sequelae (PASC). Long-term symptoms may be due to consequences from organ or tissue injury caused by SARS-CoV-2, associated clotting or inflammatory processes during acute COVID-19. Various strategies are being chosen for by clinicians to prevent severe cases of COVID-19; however, a single treatment would not be efficient in treating such a complex disease. Mesenchymal stromal cells (MSCs) are known for their immunomodulatory properties and regeneration ability; therefore, they are a promising tool for treating disorders involving immune dysregulation and extensive tissue damage, as is the case with COVID-19. This study aimed to assess the safety and explore the long-term efficacy of three intravenous doses of UC-MSCs (umbilical cord-MSCs) as an adjunctive therapy in the recovery and postacute sequelae reduction caused by COVID-19. To our knowledge, this is the first report that presents the longest follow-up after MSC treatment in COVID-19 patients. Methods: This was a phase I/II, prospective, single-center, randomized, double-blind, placebo-controlled clinical trial. Seventeen patients diagnosed with COVID-19 who require intensive care surveillance and invasive mechanical ventilation – critically ill patients – were included. The patient infusion was three doses of 5x105 cells/kg UC-MSCs, with a dosing interval of 48 hours (n=11) or placebo (n=6). These evaluations consisted of a clinical assessment, viral load, laboratory testing, including blood count, serologic, biochemical, cell subpopulation, cytokines and CT scan. Results: The results revealed that in the UC-MSC group, there was a reduction in the levels of ferritin, IL-6 and MCP1-CCL2 on the fourteen day. In the second month, a decrease in the levels of reactive C-protein, D-dimer, and neutrophils and an increase in the numbers of TCD3, TCD4 and NK lymphocytes were observed. A decrease in lung extension was observed at the fourth month. The improvement in all these parameters was maintained until the end of patient follow-up. Conclusions: UC-MSCs infusion is safe and can play an important role as an adjunctive therapy, both in the early stages, preventing severe complications and in the chronic phase with postacute sequelae reduction in critically ill COVID-19 patients. Trial registration: Brazilian Registry of Clinical Trials (ReBEC), UTN code - U1111-1254-9819. Registered 31 October 2020 - Retrospectively registered, https://ensaiosclinicos.gov.br/rg/RBR-3fz9yr

Gluteal Compartment Syndrome and Rhabdomyolysis after Prolonged Laparoscopic Nephroureterectomy and Treatment Strategies Including Rehabilitation: A Case Report

Background: Rhabdomyolysis is a clinical symptom caused by the rapid release of intracellular components such as myoglobin, lactate dehydrogenase, and creatine kinase into the blood circulation. It is commonly caused by muscular injury including compartment syndrome, infection, drugs, etc. Although it rarely occurs during surgery, the incidence may increase if risk factors such as long operation time, improper posture, and condition of being overweight exist. Case Presentation: A 46-year-old male patient complained of pain and weakness in the right hip area and several abnormal findings were observed in the blood sample, reflecting muscle injury and decreased renal function after prolonged urological surgery. He was confirmed as having rhabdomyolysis, which was caused by compartment syndrome of the right gluteal muscle. After the diagnosis, conservative cares were performed in the acute phase and rehabilitation treatments were performed in the chronic phase. After conservative treatment and rehabilitation, blood sample values returned to almost normal ranges and both level of pain and muscle strength were significantly improved. In addition, about 25 days after discharge, he almost recovered to pre-operative condition. Conclusion: Careful attention is required to prevent intraoperative compartment syndrome. It also suggests that not only medical treatment but also early patient-specific rehabilitation is important in patients with rhabdomyolysis after prolonged surgery.

The Oxidative Stress and Chronic Inflammatory Process in Chagas Disease: Role of Exosomes and Contributing Genetic Factors

Chagas disease is a neglected tropical disease caused by the flagellated protozoa Trypanosoma cruzi that affects several million people mainly in Latin American countries. Chagas disease has two phases, which are acute and chronic, both separated by an indeterminate time period in which the infected individual is relatively asymptomatic. The acute phase extends for 40-60 days with atypical and mild symptoms; however, about 30% of the infected patients will develop a symptomatic chronic phase, which is characterized by either cardiac, digestive, neurological, or endocrine problems. Cardiomyopathy is the most important and severe result of Chagas disease, which leads to left ventricular systolic dysfunction, heart failure, and sudden cardiac death. Most deaths are due to heart failure (70%) and sudden death (30%) resulting from cardiomyopathy. During the chronic phase, T. cruzi-infected macrophages respond with the production of proinflammatory cytokines and production of superoxide and nitric oxide by the NADPH oxidase 2 (NOX2) and inducible nitric oxide synthase (iNOS) enzymes, respectively. During the chronic phase, myocardial changes are produced as a result of chronic inflammation, oxidative stress, fibrosis, and cell death. The cellular inflammatory response is mainly the result of activation of the NF-κB-dependent pathway, which activates gene expression of inflammatory cytokines, leading to progressive tissue damage. The persisting production of reactive oxygen species (ROS) is the result of mitochondrial dysfunction in the cardiomyocytes. In this review, we will discuss inflammation and oxidative damage which is produced in the heart during the chronic phase of Chagas disease and recent evidence on the role of macrophages and the production of proinflammatory cytokines during the acute phase and the origin of macrophages/monocytes during the chronic phase of Chagas disease. We will also discuss the contributing factors and mechanisms leading to the chronic inflammation of the cardiac tissue during the chronic phase of the disease as well as the innate and adaptive host immune response. The contribution of genetic factors to the progression of the chronic inflammatory cardiomyopathy of chronic Chagas disease is also discussed. The secreted extracellular vesicles (exosomes) produced for both T. cruzi and infected host cells can play key roles in the host immune response, and those roles are described. Lastly, we describe potential treatments to attenuate the chronic inflammation of the cardiac tissue, designed to improve heart function in chagasic patients.

Resting-state Functional Connectivity After Occipital Stroke

Background Resting-state functional magnetic resonance imaging (rsfMRI) reflects spontaneous activation of cortical networks. After stroke, these networks reorganize, both due to structural lesion and reorganization of functional connectivity (FC). Objective We studied FC in chronic phase occipital stroke patients with homonymous visual field defects before and after repetitive transorbital alternating current stimulation (rtACS). Methods This spin-off study, embedded in the randomized, sham-controlled REVIS trial, comprised 16 chronic occipital stroke patients with visual field defect and 12 healthy control subjects. The patients underwent rsfMRI at baseline, after two weeks of rtACS or sham treatment, and after two months of treatment-free follow-up, whereas the control subjects were measured once. We used a multivariate regression connectivity model to determine mutual prediction accuracy between 74 cortical regions of interest. Additionally, the model parameters were included into a graph to analyze average path length, centrality eigenvector, centrality degree, and clustering of the network. The patients and controls at baseline and the two treatment groups were compared with multilevel modeling. Results Before treatment, the patients and controls had similar whole-network prediction accuracy and network parameters, whereas centrality eigenvector differed in perilesional regions, indicating local modification in connectivity. In line with behavioral results, neither prediction accuracy nor any network parameter changed systematically as a result of rtACS rehabilitation compared to sham. Conclusions Whole-network FC showed no difference between occipital stroke patients and healthy population, congruent with the peripheral location of the visual network in relation to the high-density cortical core. rtACS treatment in the given setting did not affect FC.