CD4+CD57+ senescent T cells as promoters of systemic lupus erythematosus pathogenesis and the therapeutic potential of senolytic BCL-2 inhibitor.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by persistent activation of immune cells and overproduction of autoantibodies. The accumulation of senescent T and B cells has been observed in SLE and other immune-mediated diseases. However, the exact mechanistic pathways contributing to this process in SLE remain incompletely understood. In this study, we found that in SLE patients: (1) the frequency of CD4+CD57+ senescent T cells was significantly elevated and positively correlated with disease activity; (2) the expression levels of B-lymphoma-2 (BCL-2) family and interferon-induced genes (ISGs) were significantly upregulated; and (3) in vitro, the cytokine IL-15 stimulation increased the frequency of senescent CD4+ T cells and upregulated the expression of BCL-2 family and ISGs. Further, treatment with ABT-263 (a senolytic BCL-2 inhibitor) in MRL/lpr mice resulted in decreased: (1) frequency of CD4+CD44hiCD62L-PD-1+CD153+ senescent CD4+ T cells; (2) frequency of CD19+CD11c+T-bet+ age-related B cells; (3) level of serum antinuclear antibody; (4) proteinuria; (5) frequency of Tfh cells; and (6) renal histopathological abnormalities. Collectively, these results indicated a dominant role for CD4+CD57+ senescent CD4+ T cells in the pathogenesis of SLE and senolytic BCL-2 inhibitor ABT-263 may be the potential treatment in ameliorating lupus phenotypes.

Disrupting B and T-cell collaboration in autoimmune disease: T-cell engagers versus CAR T-cell therapy?

B and T cells collaborate to drive autoimmune disease (AID). Historically, B- and T-cell (B-T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B-cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab, or ofatumumab. Refractory AID is a significant problem for patients with incomplete BCD with a greater frequency of IgD-CD27+ switched memory B cells, CD19+CD20- B cells, and plasma cells that are not directly targeted by anti-CD20 antibodies, whereas most lymphoid tissue plasma cells express CD19. Furthermore, B-T-cell collaboration is predominant in lymphoid tissues and at sites of inflammation such as the joint and kidney, where BCD may be inefficient, due to limited access to key effector cells. In the treatment of cancer, chimeric antigen receptor (CAR) T-cell therapy and T-cell engagers (TCE) that recruit T cells to induce B-cell cytotoxicity have delivered promising results for anti-CD19 CAR T-cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab, or epcoritamab. Limited evidence suggests that anti-CD19 CAR T-cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B-T-cell collaboration toward overcoming rituximab-resistant AID.

Long-term persistence of rituximab in patients with rheumatoid arthritis: an evaluation of the UCL cohort from 1998 to 2020.

OBJECTIVES: B cell depletion therapy based on rituximab in patients with RA was pioneered at University College London Hospitals/University College London in 1998. The objective of this study was to evaluate long-term persistence of rituximab and identify factors associated with discontinuation of treatment. METHODS: Retrospective review of medical records from all rituximab-treated RA patients followed up in a dedicated clinic (1998-2020). Data collected included gender, disease duration, previous DMARDs, autoantibody status, age and concomitant therapy at first cycle, length of follow-up, and number of cycles. Drug survival and factors associated with drug discontinuation were analysed using Kaplan-Meier survival curves, log-rank test and Cox regression analysis. RESULTS: A total of 404 patients were included. Median disease duration and age at time of first rituximab cycle were 10 and 57 years, respectively. Median total follow-up was 55 months and median number of cycles five. 93.1% of patients were seropositive. Overall, 31.2% of patients stopped rituximab, with the largest reason for discontinuing being primary inefficacy (42.1%). Comparison of Kaplan-Meier curves showed that rituximab drug survival was lower in seronegative patients and in patients who had previously failed at least one biologic DMARD (bDMARD). Cox regression analysis revealed that rituximab discontinuation was associated with a greater number of previous bDMARDs. CONCLUSION: Many patients with RA achieve good control of their disease with repeated cycles of rituximab treatment. The most common reasons for treatment discontinuation were either primary or secondary inefficacy. Patients who were seronegative and who had previously failed other bDMARDs were more at risk of drug discontinuation.

Disparity in peripheral and renal B-cell depletion with rituximab in systemic lupus erythematosus: an opportunity for obinutuzumab?

OBJECTIVES: To investigate key factors that may contribute to the variability of rituximab-mediated peripheral and renal B cell depletion (BCD) in SLE. METHODS: We analysed: (i) CD19+ B cell counts in patients with SLE before and 1, 2, 3 and 6 months after treatment with rituximab, comparing them with RA patients; (ii) the presence of B cells in renal biopsies after rituximab therapy; (iii) whether the duration of BCD correlated with patient demographics and B cell expression of CD20 and FcγRIIb; and (iv) the effect of B cell activation factor (BAFF) on the efficiency of rituximab and obinutuzumab at inducing BCD in whole blood assays, in vitro. RESULTS: In SLE (n = 71), the duration of BCD was shorter compared with RA (n = 27). B cells were detectable in renal biopsy samples (n = 6) after treatment with rituximab in all patients with poor response while peripheral blood B cells remained low or undetectable in the same patients. There were no significant relationships between peripheral BCD and patient age, disease duration, serum C3 levels or the level of expression of B cell surface proteins CD20 and FcγRIIb. Obinutuzumab was more efficient than rituximab at inducing BCD in whole blood assays, regardless of excess BAFF. CONCLUSIONS: BCD in SLE is less efficient than in RA. Renal B cell presence following rituximab treatment was associated with poor outcomes. No significant relationships between any measured B cell related, clinical or laboratory parameters and the efficiency of BCD by rituximab was found. Obinutuzumab was superior to rituximab at inducing BCD.

Anti-CD20 monoclonal antibodies in Systemic Lupus Erythematosus.

Systemic Lupus Erythematosus (SLE) is an autoimmune inflammatory condition with a wide spectrum of disease manifestations and severities, resulting in significant morbidity and mortality. The aetiopathogenesis of SLE is complex. Young women and certain ethnicities are commonly affected, suggesting a significant hormonal and genetic influence. Diverse immunological abnormalities have been described. A characteristic abnormality is the presence of autoantibodies, implicating a central role for B cells in disease pathogenesis and/or perpetuation. Whilst conventional therapies have improved outcomes, a great unmet need remains. Recently, biological therapies are being explored. B-cell depletion therapy with rituximab has been in use off-label for nearly two decades. Inconsistent results between uncontrolled and controlled studies have raised doubts about its efficacy. In this review, we will focus on B cell abnormalities and the rationale behind B-cell depletion therapy with anti-CD20 monoclonal antibody (mAb), rituximab, will be explored including an evaluation of clinical and trial experience. Finally, we will discuss the mechanistic basis for considering alternative anti-CD20 mAbs.

Day case superficial parotidectomy-does it work?

PURPOSE: To establish if day case superficial parotidectomy is feasible, safe and does not result in excess readmissions. METHOD: A retrospective review was carried out of all patients listed for superficial parotidectomy with day case intent by a single surgeon between January 2016 and December 2019 inclusively. The reasons for failure of same day discharge were established. Postoperative complications and readmissions were recorded. Our approach for a superficial parotidectomy typically includes the use of a 10Fr suction drain which is removed at 4 h postoperatively if the output is less than 30 ml. RESULTS: Ninety-one consecutive superficial parotidectomies listed for day case surgery were eligible for inclusion. Seventeen patients failed to be discharged on the same day and were admitted giving a day case success rate of 81%. Most of these (n = 9) occurred in the first year of adopting day case surgery. The most common reason to admit patients was a late finish (n = 8, 47%). Six patients (25%) were admitted due to anaesthetic complications. One patient had a surgical complication requiring admission. CONCLUSION: Our series demonstrates that day case superficial parotidectomy using a surgical drain is feasible, safe and does not result in an unacceptable readmission rate. In our experience, surgical complications are an uncommon cause for day case failure. The most common cause for day case failure was a late finish. Postoperative complications including bleeding, seroma/salivary collection and facial nerve palsy were in keeping with or better than those quoted in the literature.

Detection of Experimental and Clinical Immune Complexes by Measuring SHIP-1 Recruitment to the Inhibitory FcγRIIB.

Fc γ receptors (FcγR) are involved in multiple aspects of immune cell regulation, are central to the success of mAb therapeutics, and underpin the pathology of several autoimmune diseases. However, reliable assays capable of accurately measuring FcγR interactions with their physiological ligands, IgG immune complexes (IC), are limited. A method to study and detect IC interactions with FcγRs was therefore developed. This method, designed to model the signaling pathway of the inhibitory FcγRIIB (CD32B), used NanoLuc Binary Interaction Technology to measure recruitment of the Src homology 2 domain-containing inositol phosphatase 1 to the ITIM of this receptor. Such recruitment required prior cross-linking of an ITAM-containing activatory receptor, and evoked luciferase activity in discrete clusters at the cell surface, recapitulating the known biology of CD32B signaling. The assay detected varying forms of experimental IC, including heat-aggregated IgG, rituximab-anti-idiotype complexes, and anti-trinitrophenol-trinitrophenol complexes in a sensitive manner (≤1 µg/ml), and discriminated between complexes of varying size and isotype. Proof-of-concept for the detection of circulating ICs in autoimmune disease was provided, as responses to sera from patients with systemic lupus erythematosus and rheumatoid arthritis were detected in small pilot studies. Finally, the method was translated to a stable cell line system. In conclusion, a rapid and robust method for the detection of IC was developed, which has numerous potential applications including the monitoring of IC in autoimmune diseases and the study of underlying FcγR biology.

Mechanisms of Hypoxia in COVID-19 Patients: A Pathophysiologic Reflection.

Coronavirus disease-2019 (COVID-19) causes severe hypoxemia which fulfills the criteria of acute respiratory distress syndrome (ARDS) but is not accompanied by typical features of the syndrome. The combination of factors including low P/F ratios, high A-a gradient, relatively preserved lung mechanics, and normal pulmonary pressures may imply a process occurring on the vascular side of the alveolar-capillary unit. The scant but rapidly evolving data available on the pathophysiology are seemingly conflicting, indicating the relative dominance of intrapulmonary shunting or dead space in different studies. In this hypothesis paper, we attempt to gather and explain these observations within a unified conceptual framework by invoking the relative contributions of microvascular thrombosis, along with two proposed vascular mechanisms of capillary flow redistribution and flow through intrapulmonary arteriovenous anastomoses (IPAVA). How to cite this article: Nitsure M, Sarangi B, Shankar GH, Reddy VS, Walimbe A, Sharma V, et al. Mechanisms of Hypoxia in COVID-19 Patients: A Pathophysiologic Reflection. Indian J Crit Care Med 2020;24(10):967-970.

Obinutuzumab induces superior B-cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples.

Objective: A proportion of RA and SLE patients treated with standard doses of rituximab (RTX) display inefficient B cell deletion and poor clinical responses that can be augmented by delivering higher doses, indicating that standard-dose RTX is a sub-optimal therapy in these patients. This study aimed to investigate whether better responses could be achieved with mechanistically different anti-CD20 mAbs. Methods: We compared RTX with obinutuzumab (OBZ), a new-generation, glycoengineered type II anti-CD20 mAb, in a series of in vitro assays measuring B cell cytotoxicity in RA and SLE patient samples. Results: We found that OBZ was at least 2-fold more efficient than RTX at inducing B-cell cytotoxicity in in vitro whole blood assays. Dissecting this difference, we found that RTX elicited more potent complement-dependent cellular cytotoxicity than OBZ. In contrast, OBZ was more effective at evoking Fc gamma receptor-mediated effector mechanisms, including activation of NK cells and neutrophils, probably due to stronger interaction with Fc gamma receptors and the ability of OBZ to remain at the cell surface following CD20 engagement, whereas RTX became internalized. OBZ was also more efficient at inducing direct cell death. This was true for all CD19 + B cells as a whole and in naïve (IgD + CD27 - ) and switched (IgD - CD27 + ) memory B cells specifically, a higher frequency of which is associated with poor clinical response after RTX. Conclusion: Taken together, these data provide a mechanistic basis for resistance to rituximab-induced B-cell depletion, and for considering obinutuzumab as an alternative B-cell depleting agent in RA and SLE.

The water penetration of different ventilation tubes.

The insertion of middle ear ventilation tubes remains one of the most common procedures for ENT surgeons. A common concern amongst patients undergoing such procedures is the effect on their ability to partake in swimming and other water sports. Currently there is little evidence comparing the penetration ability of different water solutions encountered by swimmers. This study compares the water penetration of four different water solutions for Shah, mini-Shah, T tube and titanium bobbin ventilation tubes. A model was constructed to replicate a grommet inserted through a tympanic membrane using a syringe barrel, latex membrane and one of the ventilation tubes. Four solutions (sea water, chlorinated water, freshwater and soapy water) were then pipetted down the barrel until penetration of the tube occurred. The volume required for penetration was recorded. For all tubes soapy water was the most penetrating, followed by seawater. Titanium bobbins required significantly less of each solution for penetration. Mini-Shah grommets required significantly more of all solutions except soapy water for penetration to occur. Shah grommets were more resistant to chlorinated and sea water than T tubes. Mini-Shah grommets appear to protect against water penetration into the middle ear cleft and their use should be considered in patients who are keen water-sport enthusiasts. Furthermore, swimmers in sea or chlorinated water seem to be at higher risk than freshwater swimmers. Titanium bobbins were relatively easily penetrated by all four solutions and should be avoided in keen swimmers.

Post-burn Cervicofacial Necrotizing Fasciitis With Diabetic Ketoacidosis: A Report of a Case With a Favorable Outcome.

Post-burn necrotizing fasciitis (PBNF) is a serious and potentially life-threatening infection that occurs after a burn injury. It is characterized by rapid destruction of soft tissue and muscle and is usually caused by a bacterial infection. Diabetic ketoacidosis (DKA) is another serious complication of diabetes, which can occur when the body does not have enough insulin to break down glucose for energy. This causes the body to start breaking down fat for energy instead, leading to various complications. The present study discusses the association between PBNF and DKA in a patient with diabetes. Here is a case of a post-auricular abscess and a precipitated DKA. The abscess was located near the site of the previous burn injury that happened 20 years ago and was believed to have developed as a result of thick scar tissue. The patient was given adequate hydration, intravenous antibiotics, and insulin therapy. However, the abscess continued to grow with increasing insulin requirements and the patient underwent incision and drainage to remove the infected tissue, and an aggressive debridement was carried out. Thus, this case highlights the importance of closely monitoring blood sugar levels in patients with a history of burn injury and diabetes, as well as the potential for infections to precipitate DKA. Timely intervention, including incision and drainage, can lead to successful resolution of symptoms and improved outcomes.

Navigating the Complexity of Scoring Systems in Sepsis Management: A Comprehensive Review.

This comprehensive review navigates the intricate landscape of sepsis scoring systems, aiming to provide healthcare professionals and researchers with a nuanced understanding of their role in contemporary sepsis management. Beginning with a succinct overview of sepsis, the review emphasizes the significance of scoring systems in standardizing assessments and guiding clinical decision-making. Through a detailed analysis of prominent systems such as SOFA, APACHE, and qSOFA, the review delineates their unique attributes, strengths, and limitations. The implications for sepsis management and patient outcomes are discussed, highlighting the potential for these tools to enhance early detection and intervention. The review concludes with a compelling call to action, urging healthcare professionals to integrate scoring systems into routine practice and researchers to explore novel approaches. By synthesizing current knowledge and addressing future directions, this review serves as a valuable resource for those seeking clarity and guidance in the dynamic landscape of sepsis management.

Metronidazole-Induced Acute Cerebellitis in a Young Patient: Unusual Onset, Delayed Remission, and Characteristic Imaging Features.

Metronidazole-induced acute cerebellitis is an exceptionally rare condition resulting from severe adverse reactions to metronidazole, a medication generally employed in the management of infections caused by anaerobic microbes. Although neuropathy has been linked to metronidazole use, reports of acute cerebellitis are infrequent. The neurological effects associated with metronidazole can include weakness, dysarthria, postural instability, seizures, giddiness, vertigo, ataxia, confusion, encephalopathy, headaches, and tremors. The onset of cerebellitis can vary, occurring as early as one day or after several weeks of metronidazole treatment. This article presents a case of a young girl who presented to us with weakness in both upper and lower limbs, dysarthria, and postural instability after exposure to 12 grams of metronidazole (suicidal, 30 tablets of 400 mg). With the above-mentioned complaints, the patient was advised of magnetic resonance imaging of the brain, which showed the features of cerebellitis.

A national research survey of childhood autism assessment services in the UK: empirical evidence of diagnostic practice, challenges and improvement opportunities.

BACKGROUND: The UK National Health Service (NHS) Long Term Plan aims to reduce waiting times for childhood autism diagnostic assessment and improve parent and child satisfaction. This empirical research investigated current childhood diagnostic practice provision, and changes made by teams to address challenges faced. METHODS: Data were collected using an online semi-structured research questionnaire. UK childhood autism diagnostic assessment services (for children aged 1-18 years) were invited to participate through multidisciplinary clinical networks, special interest groups and professionals mailing lists. The study was on the National Institute for Health Research Clinical Research Network portfolio. RESULTS: 128 clinicians from diverse NHS services responded including: 10 (8%) integrated services, 46 (36%) Child and Adolescent Mental Health Services (CAMHS) and 72 (56%) paediatric services. A minority of services (23, 17.9%) reported always meeting the National Institute for Health and Care Excellence guidance for assessment. Referrals rose 115% between 2015 and 2019. Clinicians described increased child and family complexity compared with previously; children had more co-occurring physical, mental health and neurodevelopmental conditions and there were more frequent family health problems and safeguarding concerns. Most services (97, 75.8%) reported recent funding stayed constant/decreased. Incomplete multidisciplinary teams (MDTs) were frequently reported; a minority of services reported increased availability of professionals, and some experienced reductions in key professionals. Many teams were unable to undertake assessments or make recommendations for associated neurodevelopmental and co-existing conditions. Teams described improvement strategies implemented (eg, adapting professionals' roles, supporting parents). CONCLUSIONS: Most UK autism paediatric and CAMHS diagnostic teams experience significant challenges affecting the assessment of children with possible autism, and recommendations regarding treatment/intervention. Where CAMHS or paediatric services work in isolation, there are often competency gaps in MDTs and ability to deliver full neurodevelopmental and mental health assessments. Teams identified service improvement strategies; however, investment in MDT expertise is required to enable services to implement changes to meet the needs of children and families.

Topical application of a BCL-2 inhibitor ameliorates imiquimod-induced psoriasiform dermatitis by eliminating senescent cells.

BACKGROUND: Psoriasis is an inflammatory skin disease with unclear pathogenesis and unmet therapeutic needs. OBJECTIVE: To investigate the role of senescent CD4+ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis. METHODS: We explored the expression levels of p16INK4a and p21, classical markers of cellular senescence, in CD4+ T cells from human psoriatic lesions and imiquimod (IMQ)-induced psoriatic lesions. We prepared a senolytic gel using B-cell lymphoma 2 (BCL-2) inhibitor ABT-737 and evaluated its therapeutic efficacy in treating psoriasis. RESULTS: Using multispectrum immunohistochemistry (mIHC) staining, we detected increased expression levels of p16INK4a and p21 in CD4+ T cells from psoriatic lesions. After topical application of ABT-737 gel, significant alleviation of IMQ-induced psoriatic lesions was observed, with milder pathological alterations. Mechanistically, ABT-737 gel significantly decreased the percentage of senescent cells, expression of T cell receptor (TCR) α and ß chains, and expression of Tet methylcytosine dioxygenase 2 (Tet2) in IMQ-induced psoriatic lesions, as determined by mIHC, high-throughput sequencing of the TCR repertoire, and RT-qPCR, respectively. Furthermore, the severity of psoriatic lesions in CD4creTet2f/f mice was milder than that in Tet2f/f mice in the IMQ-induced psoriasis model. CONCLUSION: We revealed the roles of senescent CD4+ T cells in developing psoriasis and highlighted the therapeutic potential of topical ABT-737 gel in treating psoriasis through the elimination of senescent cells, modulation of the TCR αß repertoire, and regulation of the TET2-Th17 cell pathway.

A 10-Year Retrospective Review of the Histology of Symptomatic and Asymptomatic Unilateral Nasal Polyps.

Background The aim of this study was to determine the histological diagnosis of unilateral nasal polyps and to determine the prevalence of neoplastic pathologies. This study also assessed difference in pathologies whether patients presented symptomatically or were asymptomatic (if they had a mass found incidentally for unrelated throat symptoms).  Method This was a 10-year retrospective study of patients undergoing unilateral nasal mass surgery between 2004 and 2014 at a UK district general hospital. We recorded patient demographics, laterality, histology, symptoms, clinical suspicion, and imaging findings. Results  123 patients were included who underwent unilateral surgery between 2004 and 2014 (male n=83, female n=40; mean age 56 years ± 19.5). The majority were of inflammatory origin (n=92; 74.8%). The most common benign neoplastic cause was inverted papilloma (n=19; 15.4%). A number of malignant neoplastic causes were also found, including: melanoma (n=3; 2.44%), olfactory neuroblastoma (n=2; 1.63%), and other non-inflammatory masses (n=7; 5.69%). 15 of these masses were found incidentally, with 14 being inflammatory, and one an olfactory neuroblastoma; therefore, 6.67% of our incidental unilateral nasal masses were found to be of neoplastic pathology. Conclusion This study's findings support the continued practice of routine biopsy of unilateral nasal masses for histological diagnosis, irrespective of whether they are symptomatic or found incidentally. The accuracy of both clinical suspicion and radiological suspicion on CT scans is not adequate to alter this practice.

Pantothenate Kinase-Associated Neurodegeneration (PKAN) With Concomitant Blepharospasm: Unveiling a Clinical Enigma.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare and complex neurodegenerative disorder. It occurs due to mutations in the sequencing of the PANK2 gene. Here, we describe the case of a 22-year-old male patient who presented with severe blepharospasm; he had abnormal facial distortions, shaky limbs, rigid muscles, and a slow pace of movement, making a diagnosis tricky. Accumulation of iron in excessive amounts in the basal ganglia, a part of the brain that governs movement, is linked to PKAN. In this case, the "eye of the tiger" indication, a distinctive pattern only seen by MRI, supported PKAN. The anticholinergic medications helped him alleviate his symptoms to some extent, but he still had some degree of impairment. This instance emphasizes the mysterious character of PKAN and the significance of keeping an eye out for unusual symptoms in neurodegenerative conditions. This case report emphasizes the significance of recognizing unexpected effects that brain disorders can have on people's lives and calls for increased clinician awareness and understanding.

Beyond the Shadows: Unravelling the Menace of Methanol-Induced Posterior Reversible Encephalopathy Syndrome.

Posterior reversible encephalopathy syndrome (PRES) is a clinical-radiological illness characterized by neurological symptoms and reversible changes in neuroimaging. We discuss the case of a 45-year-old patient with an alcohol use disorder who presented with an altered mental state in the emergency room. Home-made alcohol, known to contain significant quantities of methanol, was recently consumed in excess by the said patient. The diagnosis of PRES was supported by magnetic resonance imaging (MRI), which showed bilateral hyperintense regions in the temporo-occipital lobes and diffuse cerebral edema. The development of PRES and chronic alcoholism, as well as binge drinking and possible endothelial dysfunction, are all highlighted in this case study. For individuals with PRES, early identification and adequate care are essential for reducing complications and improving outcomes.

Vestibular, Central, and Non-Vestibular Etiologies of Vertigo and Disequilibrium: A Rural Hospital-Based Cross-Sectional Comparative Analysis.

INTRODUCTION: Vertigo/dizziness is defined as disturbed postural awareness and could range from a feeling of sensation of spinning of self or surrounding. Dizziness or disturbed postural awareness is a common presentation in varying age groups. Vertigo has varied clinical presentations. Classically, there are four vertigo syndromes: vertigo, imbalance/disequilibrium, presyncope/lightheadedness, and psychogenic dizziness. The present study was conducted to examine the various etiologies involved in these syndromes and to help unmask the overlaps between them. This study also aimed to further classify the etiologies underlying these vertigo syndromes and overlaps into peripheral or vestibular, central, and non-vestibular. This would help develop a comprehensive management protocol for vertigo of any origin. METHODS: A prospective observational cross-sectional study was undertaken in a rural hospital in Central India. We studied patients with giddiness and categorized them into vertigo syndromes according to the site of origin of vertigo. We also compared overlaps in the presentation of vertigo. RESULTS: Out of the 80 patients that were studied, vertigo with disequilibrium was observed in 72.50% of the patients. Non-vestibular vertigo of cervicogenic origin was the common cause of vertigo seen in 36.25% of the patients occurring alone or in association with vestibular vertigo. Among patients with overlaps, vestibular vertigo with non-vestibular vertigo was the most common etiology observed in 89.65% of the patients with overlaps. CONCLUSION: The syndrome of "vertigo with disequilibrium" was the commonest presentation in the patients studied, followed by "vertigo syndrome" as an isolated symptom, not associated with "disequilibrium." Ours is probably the first study to report this observation of overlaps of two syndromes, with diagnostic implications.

In vitro B cell experiments explore the role of CD24, CD38, and energy metabolism in ME/CFS.

Introduction: Disturbances of energy metabolism contribute to the clinical manifestations of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Previously, we found that B cells from ME/CFS patients have an increased expression of CD24, a modulator of many cellular functions including those of cell stress. The relative ability of B cells from ME/CFS patients and healthy controls (HC) to respond to rapid changes in energy demand was compared. Methods: CD24, the ectonucleotidases CD39 and CD73, the NAD-degrading enzyme CD38, and mitochondrial mass (MM) were measured following cross-linking of the B cell receptor and costimulation with either T-cell-dependent or Toll-like-receptor-9-dependent agonists. The levels of metabolites consumed/produced were measured using 1H-NMR spectroscopy and analyzed in relation to cell growth and immunophenotype. Results: Proliferating B cells from patients with ME/CFS showed a lower mitochondrial mass and a significantly increased usage of essential amino acids compared with those from HC, with a significantly delayed loss of CD24 and an increased expression of CD38 following stimulation. Discussion: The immunophenotype results suggested the triggering of a stress response in ME/CFS B cells associated with the increased usage of additional substrates to maintain necessary ATP levels. Disturbances in energy metabolism in ME/CFS B cells were thus confirmed in a dynamic in vitro model, providing the basis for further mechanistic investigations.