Druggable monogenic immune defects hidden in diverse medical specialties: Focus on overlap syndromes

In the last two decades two new paradigms changed our way of perceiving primary immunodeficiencies: An increasing number of immune defects are more associated with inflammatory or autoimmune features rather than with infections. Some primary immune defects are due to hyperactive pathways that can be targeted by specific inhibitors, providing innovative precision treatments that can change the natural history of diseases. In this article we review some of these "druggable" inborn errors of immunity and describe how they can be suspected and diagnosed in diverse pediatric and adult medicine specialties. Since the availability of precision treatments can dramatically impact the course of these diseases, preventing the development of organ damage, it is crucial to widen the awareness of these conditions and to provide practical hints for a prompt detection and cure

Simple and Rapid Non-Enzymatic Procedure Allows the Isolation of Structurally Preserved Connective Tissue Micro-Fragments Enriched with SVF

The stromal vascular fraction (SVF) consists of a heterogeneous population of stem and stromal cells, generally obtained from adipose tissue by enzymatic digestion. For human cell-based therapies, mechanical process methods to obtain SVF represent an advantageous approach because they have fewer regulatory restrictions for their clinical use. The aim of this study was to characterize a novel commercial system for obtaining SVF from adipose tissue by a mechanical approach without substantial manipulations. Lipoaspirate samples collected from 27 informed patients were processed by a simple and fast mechanical system (by means of Hy-Tissue SVF). The Hy-Tissue SVF product contained a free cell fraction and micro-fragments of stromal connective tissue. The enzymatic digestion of the micro-fragments increased the yield of free cells (3.2 times) and CFU-F (2.4 times). Additionally, 10% of free cells from SVF were positive for CD34+, suggesting the presence of endothelial cells, pericytes, and potential adipose-derived stem cells (ADSC). Moreover, the SVF cells were able to proliferate and differentiate in vitro toward adipocytes, osteocytes, and chondrocytes. The immunophenotypic analysis of expanded cells showed positivity for typical mesenchymal stem cell markers. The Hy-Tissue SVF system allows the isolation of stromal vascular fraction, making this product of potential interest in regenerative medicine

Usability of a Hybrid System Combining P300-Based Brain-Computer Interface and Commercial Assistive Technologies to Enhance Communication in People With Multiple Sclerosis

Brain-computer interface (BCI) can provide people with motor disabilities with an alternative channel to access assistive technology (AT) software for communication and environmental interaction. Multiple sclerosis (MS) is a chronic disease of the central nervous system that mostly starts in young adulthood and often leads to a long-term disability, possibly exacerbated by the presence of fatigue. Patients with MS have been rarely considered as potential BCI end-users. In this pilot study, we evaluated the usability of a hybrid BCI (h-BCI) system that enables both a P300-based BCI and conventional input devices (i.e., muscular dependent) to access mainstream applications through the widely used AT software for communication "Grid 3." The evaluation was performed according to the principles of the user-centered design (UCD) with the aim of providing patients with MS with an alternative control channel (i.e., BCI), potentially less sensitive to fatigue. A total of 13 patients with MS were enrolled. In session I, participants were presented with a widely validated P300-based BCI (P3-speller); in session II, they had to operate Grid 3 to access three mainstream applications with (1) an AT conventional input device and (2) the h-BCI. Eight patients completed the protocol. Five out of eight patients with MS were successfully able to access the Grid 3 via the BCI, with a mean online accuracy of 83.3% (+/- 14.6). Effectiveness (online accuracy), satisfaction, and workload were comparable between the conventional AT inputs and the BCI channel in controlling the Grid 3. As expected, the efficiency (time for correct selection) resulted to be significantly lower for the BCI with respect to the AT conventional channels (Z = 0.2, p < 0.05). Although cautious due to the limited sample size, these preliminary findings indicated that the BCI control channel did not have a detrimental effect with respect to conventional AT channels on the ability to operate an AT software (Grid 3). Therefore, we inferred that the usability of the two access modalities was comparable. The integration of BCI with commercial AT input devices to access a widely used AT software represents an important step toward the introduction of BCIs into the AT centers' daily practice

In vitro characterization of adipose stem cells non-enzymatically extracted from the thigh and abdomen

Autologous fat grafting is a surgical technique in which adipose tissue is transferred from one area of the body to another, in order to reconstruct or regenerate damaged or injured tissues. Before reinjection, adipose tissue needs to be purified from blood and cellular debris to avoid inflammation and preserve the graft viability. To perform this purification, different enzymatic and mechanical methods can be used. In this study, we characterized in vitro the product of a closed automatic device based on mechanical disaggregation, named Rigenera\uae, focusing on two sites of adipose tissue harvesting. At first, we optimized the Rigenera\uae operating timing, demonstrating that 60 s of treatment allows a higher cellular yield, in terms of the cell number and growth rate. This result optimizes the mechanical disaggregation and it can increase the clinical efficiency of the final product. When comparing the extracted adipose samples from the thigh and abdomen, our results showed that the thigh provides a higher number of mesenchymal-like cells, with a faster replication rate and a higher ability to form colonies. We can conclude that by collecting adipose tissue from the thigh and treating it with the Rigenera\uae device for 60 s, it is possible to obtain the most efficient product

Use of a Custom-Made Patellar Groove Replacement in an American Staffordshire Terrier Puppy with a Severe Bone Defect in the Femoral Trochlea Caused by Hematogenous Osteomyelitis

Simple Summary Osteomyelitis is a bone infection disease causing progressive inflammation. Bone lysis, periosteal reactions and ischemic regions of infected necrotic and devitalized tissue are likely secondary abnormalities. A prolonged antibiotic therapy, an abundant lavage of the affected region and several revision surgeries to debride infected and necrotic bone are paramount treatments for osteomyelitis. The treatment of extensive bone defects and functional damage may require the use of prosthetic surgery, allowing the anatomical and functional recovery of the affected area, and in some cases, it is necessary to use a customized prosthesis for a better anatomical and functional adaptation. In veterinary medicine, the implementation of 3D-printing technologies and the application of custom-made surgical implants and prosthetics have enabled the management of intricate orthopedic conditions that were previously only addressed through salvage procedures, such as arthrodesis or amputations. The purpose of this report is to describe the surgical technique and outcome of a custom-made patellar groove replacement in a puppy with a severe bone defect in the femoral trochlea caused by hematogenous osteomyelitis. This surgery showed excellent short-, medium- and long-term outcomes, and it is the first report on a custom-made patellar groove replacement available in the literature.Abstract An 8-month-old male American Staffordshire terrier was referred for a no-weightbearing lameness of the right pelvic limb, hyperthermia, lethargy and inappetence. Two months before, endocarditis was diagnosed and treated in another veterinary hospital. Orthopedic, radiographic and tomographic examinations revealed a bone sequestrum of 4 x 1.4 cm and active periosteal reaction of the caudo-lateral cortical in the metaphysis and the distal third of the right femoral diaphysis, medullary osteolysis and interruption of the cranio-medial cortical profile, with involvement of the femoral trochlea leading to a secondary medial patella luxation. Hematogenous osteomyelitis was the suspected diagnosis. Once skeletally mature, after 4 months from surgical debridement and aggressive antibiotic therapy against Klebsiella oxytoca revealed by a bacteriological exam, the patient underwent prosthetic surgery for the application of a custom-made patellar groove replacement (PGR) to fill the bone defect and restore the femoral trochlea surface. Despite the serious injury that afflicted the right pelvic limb, the surgery had satisfactory outcomes until the last 18-month postoperative follow up

EEG-based Brain-Computer Interfaces for people with Disorders of Consciousness: Features and applications. A systematic review

Background: Disorders of Consciousness (DoC) are clinical conditions following a severe acquired brain injury (ABI) characterized by absent or reduced awareness, known as coma, Vegetative State (VS)/Unresponsive Wakefulness Syndrome (VS/UWS), and Minimally Conscious State (MCS). Misdiagnosis rate between VS/UWS and MCS is attested around 40% due to the clinical and behavioral fluctuations of the patients during bedside consciousness assessments. Given the large body of evidence that some patients with DoC possess "covert" awareness, revealed by neuroimaging and neurophysiological techniques, they are candidates for intervention with brain-computer interfaces (BCIs). Objectives: The aims of the present work are (i) to describe the characteristics of BCI systems based on electroencephalography (EEG) performed on DoC patients, in terms of control signals adopted to control the system, characteristics of the paradigm implemented, classification algorithms and applications (ii) to evaluate the performance of DoC patients with BCI. Methods: The search was conducted on Pubmed, Web of Science, Scopus and Google Scholar. The PRISMA guidelines were followed in order to collect papers published in english, testing a BCI and including at least one DoC patient. Results: Among the 527 papers identified with the first run of the search, 27 papers were included in the systematic review. Characteristics of the sample of participants, behavioral assessment, control signals employed to control the BCI, the classification algorithms, the characteristics of the paradigm, the applications and performance of BCI were the data extracted from the study. Control signals employed to operate the BCI were: P300 (N = 19), P300 and Steady-State Visual Evoked Potentials (SSVEP; hybrid system, N = 4), sensorimotor rhythms (SMRs; N = 5) and brain rhythms elicited by an emotional task (N = 1), while assessment, communication, prognosis, and rehabilitation were the possible applications of BCI in DoC patients. Conclusion: Despite the BCI is a promising tool in the management of DoC patients, supporting diagnosis and prognosis evaluation, results are still preliminary, and no definitive conclusions may be drawn; even though neurophysiological methods, such as BCI, are more sensitive to covert cognition, it is suggested to adopt a multimodal approach and a repeated assessment strategy

Ultrasound and Elastosonographic Features of the Patellar Ligament in Dogs Affected by Cranial Cruciate Ligament Disease

Simple Summary In patients suffering from cranial cruciate ligament disease, the patellar ligament is loaded aphysiologically, resulting in increased stress. To date, however, there have been no studies describing the establishment of anatomical or functional damage to this ligament after cranial cruciate ligament disease. This study aims to evaluate the appearance of the patellar ligament using ultrasound and elastosonography in dogs affected by disease of the cranial cruciate ligament but not yet treated in order to understand whether signs of thickening and a reduction in elasticity increase over time between the day of ligament disease onset and the day of diagnosis and therefore persist before being treated with the surgical procedure of tibial plateau leveling osteotomy or tibial tuberosity advancement. The results suggest that as the time increases between the onset of cranial cruciate ligament disease and diagnosis and treatment, the patellar ligament progressively thickens and has a tendency to lose its elasticity.Abstract This study aims to evaluate the morpho-functional change in the patellar ligament in dogs with cranial cruciate ligament disease. We hypothesized that it may show increased thickening and stiffness with increasing days from onset to diagnosis instead of trauma. Understanding this aspect has implications for the choice of timing for treating patients suffering from cranial cruciate ligament disease, as well as the contextualization of patellar ligament desmitis pictures after surgical treatment with tibial plateau leveling osteotomy or tibial tuberosity advancement. Thirty-three dogs affected by unilateral cranial cruciate disease were examined and divided into three groups based on the time elapsed from the onset of lameness to diagnosis: Group 1 (1-15 days), Group 2 (16-60 days), and Group 3 (over 60 days). Conventional B-mode ultrasonographic and elastosonographic examinations of the patellar ligament were performed without sedation for each dog. Upon ultrasonographic examination, all dogs showed modification in the echostructure of the patellar ligament. In addition, the patellar ligament tended to become harder with increasing days after disease, although there were no significant differences between groups. Our results show that as the time increases between the onset of cranial cruciate ligament disease and diagnosis and treatment, the patellar ligament progressively thickens and loses its elasticity

Genetic test for the channelopaties: useful or less than useful for patients? (part 2.)

The advanced knowledge about genetic diseases and their mutations has widened the possibility to have a more precise and definitive diagnosis in many patients, but the use of genetic testing is still controversial. Actually, many cardiomyopathies show the availability of genetic testing. The clinical utility of this testing has been widely debated, but it is evident that the use of genetics must be put in a more organic diagnostic pathway that includes the evaluation of risks and benefits for the patient and his relatives, as well as the costs of the procedure. This review aims to clarify the role of genetic in clinics regarding Channelopaties, less frequent but equally important than other Cardiomyopathies because patients can often be asymptomatic until the first fatal manifestation

Comparative study of 1H-NMR metabolomic profile of canine synovial fluid in patients affected by four progressive stages of spontaneous osteoarthritis

The study aimed to assess the metabolomic profile of the synovial fluid (SF) of dogs affected by spontaneous osteoarthritis (OA) and compare any differences based on disease progression. Sixty client-owned dogs affected by spontaneous OA underwent clinical, radiographic, and cytologic evaluations to confirm the diagnosis. The affected joints were divided into four study groups based on the Kallgreen-Lawrence classification: OA1 (mild), OA2 (moderate), OA3 (severe), and OA4 (extremely severe/deforming). The osteoarthritic joint's SF was subjected to cytologic examination and H-1-NMR analysis. The metabolomic profiles of the study groups' SF samples were statistically compared using one-way ANOVA. Sixty osteoarthritic joints (45 stifles, 10 shoulders and 5 elbows) were included in the study. Fourteen, 28, and 18 joints were included in the OA1, OA2, and OA3 groups, respectively (0 joints in the OA4 group). Metabolomic analysis identified 48 metabolites, five of which were significantly different between study groups: Mannose and betaine were elevated in the OA1 group compared with the OA2 group, and the 2-hydroxyisobutyrate concentration decreased with OA progression; in contrast, isoleucine was less concentrated in mild vs. moderate OA, and lactate increased in severe OA. This study identified different H-1-NMR metabolomic profiles of canine SF in patients with progressive degrees of spontaneous OA, suggesting H-1-NMR metabolomic analysis as a potential alternative method for monitoring OA progression. In addition, the results suggest the therapeutic potentials of the metabolomic pathways that involve mannose, betaine, 2-hydroxyisobutyrate, isoleucine, and lactate