Clinical and laboratory features of seventy-eight UK patients with Good’s syndrome (thymoma and hypogammaglobulinaemia)

Good’s syndrome (thymoma and hypogammaglobulinaemia) is a rare secondary immunodeficiency disease, previously reported in the published literature as mainly individual cases or small case series. We use the national UK-Primary Immune Deficiency (UKPID) registry to identify a large cohort of patients in the UK with this PID to review its clinical course, natural history and prognosis. Clinical information, laboratory data, treatment and outcome were collated and analysed. Seventy-eight patients with a median age of 64 years, 59% of whom were female, were reviewed. Median age of presentation was 54 years. Absolute B cell numbers and serum immunoglobulins were very low in all patients and all received immunoglobulin replacement therapy. All patients had undergone thymectomy and nine (12%) had thymic carcinoma (four locally invasive and five had disseminated disease) requiring adjuvant radiotherapy and/or chemotherapy. CD4 T cells were significantly lower in these patients with malignant thymoma. Seventy-four (95%) presented with infections, 35 (45%) had bronchiectasis, seven (9%) chronic sinusitis, but only eight (10%) had serious invasive fungal or viral infections. Patients with AB-type thymomas were more likely to have bronchiectasis. Twenty (26%) suffered from autoimmune diseases (pure red cell aplasia, hypothyroidism, arthritis, myasthenia gravis, systemic lupus erythematosus, Sjögren’s syndrome). There was no association between thymoma type and autoimmunity. Seven (9%) patients had died. Good’s syndrome is associated with significant morbidity relating to infectious and autoimmune complications. Prospective studies are required to understand why some patients with thymoma develop persistent hypogammaglobulinaemia.     

Def-2, -3, -6 and -8, novel mouse genes differentially expressed in the haemopoietic system

To identify developmentally regulated genes during myeloid differentiation, a self-inactivating retroviral gene-trap vector carrying a beta-galactosidase-neomycin (SA/lacZ/neo) fusion gene was constructed and used to infect myeloid progenitor cells (FDCP-Mix A4). G418-resistant and beta-galactosidase positive cell lines (gene-trap integration [GTI] clones) were established and induced to differentiate in vitro into either macrophages or granulocytes. Expression of the trapped loci was monitored at a single-cell level by analysing the mature cell types for beta-galactosidase activity. All 37 GTI clones tested showed down-regulation either during granulocyte or both granulocytic and macrophage differentiation. The endogenous coding regions fused to the SA/lacZ/neo reporter gene were isolated from eight clones. Molecular analysis revealed that half of them represented novel mouse genes (def-2, -3, -6 and -8) which we confirmed to be differentially expressed in primary haemopoietic tissues. Database searches revealed no significant similarities for def-2 (associated with haemopoietic progenitors) and def-8 (expressed most strongly in peripheral leucocytes). Def-6, which is down-regulated upon the differentiation into myeloid as well as erythroid lineages, was found to be closely related but not identical with the recently described B-cell-specific switch recombinase SWAP-70. Def-3, which is down-regulated upon differentiation into granulocytes but expressed in progenitor cells and macrophages, defines a novel family of RNA binding proteins.     

Coronavirus Pseudotypes for All Circulating Human Coronaviruses for Quantification of Cross-Neutralizing Antibody Responses

The novel coronavirus SARS-CoV-2 is the seventh identified human coronavirus. Understanding the extent of pre-existing immunity induced by seropositivity to endemic seasonal coronaviruses and the impact of cross-reactivity on COVID-19 disease progression remains a key research question in immunity to SARS-CoV-2 and the immunopathology of COVID-2019 disease. This paper describes a panel of lentiviral pseudotypes bearing the spike (S) proteins for each of the seven human coronaviruses (HCoVs), generated under similar conditions optimized for high titre production allowing a high-throughput investigation of antibody neutralization breadth. Optimal production conditions and most readily available permissive target cell lines were determined for spike-mediated entry by each HCoV pseudotype: SARS-CoV-1, SARS-CoV-2 and HCoV-NL63 best transduced HEK293T/17 cells transfected with ACE2 and TMPRSS2, HCoV-229E and MERS-CoV preferentially entered HUH7 cells, and CHO cells were most permissive for the seasonal betacoronavirus HCoV-HKU1. Entry of ACE2 using pseudotypes was enhanced by ACE2 and TMPRSS2 expression in target cells, whilst TMPRSS2 transfection rendered HEK293T/17 cells permissive for HCoV-HKU1 and HCoV-OC43 entry. Additionally, pseudotype viruses were produced bearing additional coronavirus surface proteins, including the SARS-CoV-2 Envelope (E) and Membrane (M) proteins and HCoV-OC43/HCoV-HKU1 Haemagglutinin-Esterase (HE) proteins. This panel of lentiviral pseudotypes provides a safe, rapidly quantifiable and high-throughput tool for serological comparison of pan-coronavirus neutralizing responses; this can be used to elucidate antibody dynamics against individual coronaviruses and the effects of antibody cross-reactivity on clinical outcome following natural infection or vaccination.     

THE VAXED PROJECT: An Assessment of Immunization Education in Canadian Health Professional Programs

Background  

Knowledge & attitudes of healthcare providers (HCP) have significant impact on frequency with which vaccines are offered & accepted but many HCP are ill equipped to make informed recommendations about vaccine merits & risks. We performed an assessment of the educational needs of trainees regarding immunization and used the information thus ascertained to develop multi-faceted, evaluable, educational tools which can be integrated into formal education curricula.     

Bite force, endurance and masseter muscle fatigue in healthy edentulous subjects and those with TMD

It is well known that bite force and EMG activity are considerably reduced in edentulous patients, but the susceptibility of their jaw-closing muscles to localized fatigue is less certain. This information is even less clear for edentulous subjects who have TMD. Eleven healthy edentulous subjects and 10 edentulous subjects with TMD participated in this study. Maximum bite force was measured first, with the transducer placed on the canine-first premolar region bilaterally, and then two rapid relaxations were made from a brief voluntary clench to 50% of maximum. A sustained voluntary clench of 50% of maximum was then maintained and endurance time was noted. EMG was recorded from both masseter muscles and the median frequency of the power spectrum of the EMG from 2 s at the beginning of the sustained clench and 2 s at the end was subsequently calculated. Two more rapid relaxations from brief clenches were performed immediately after the sustained clench. The mean maximum bite force in the healthy group was 115 N (SD +/-41) and in the TMD group was 75 N (SD +/-22), this difference being significant (P = 0.0013). The mean endurance time in the healthy group was 86 s (SD +/-51) and in the TMD group was 63 s (SD +/-20). The percentage change in the median frequency in the healthy group as a result of the sustained contraction was 6% (left) and 8.6% (right) and in the TMD group was 13.9% (left) and 12.8% (right). The percentage change in the mean relaxation half time for the healthy group was 28.5% and for the TMD group was 72%, a significant difference (P = 0.0046). It was apparent that the maximum bite force was low in edentulous subjects and was further reduced in edentulous TMD subjects; endurance time was reduced in TMD subjects; fatigue resistance of the masseter muscles was reduced in TMD subjects.     

A screen of pharmacologically active compounds to identify modulators of the Adgrg6/Gpr126 signalling pathway in zebrafish embryos

Adhesion G protein-coupled receptors (GPCRs) are an underrepresented class of GPCRs in drug discovery. We previously developed an in vivo drug screening pipeline to identify compounds with agonist activity for Adgrg6 (Gpr126), an adhesion GPCR required for myelination of the peripheral nervous system in vertebrates. The screening assay tests for rescue of an ear defect found in adgrg6^{tb233c−/−} hypomorphic homozygous mutant zebrafish, using the expression of versican b (vcanb) mRNA as an easily identifiable phenotype. In the current study, we used the same assay to screen a commercially available library of 1280 diverse bioactive compounds (Sigma LOPAC). Comparison with published hits from two partially overlapping compound collections (Spectrum, Tocris) confirms that the screening assay is robust and reproducible. Using a modified counter screen for myelin basic protein (mbp) gene expression, we have identified 17 LOPAC compounds that can rescue both inner ear and myelination defects in adgrg6^{tb233c−/−} hypomorphic mutants, three of which (ebastine, S-methylisothiourea hemisulfate, and thapsigargin) are new hits. A further 25 LOPAC hit compounds were effective at rescuing the otic vcanb expression but not mbp. Together, these and previously identified hits provide a wealth of starting material for the development of novel and specific pharmacological modulators of Adgrg6 receptor activity.     

Acoustic myography, electromyography and bite force in the masseter muscle

Acoustic myography (AMG) offers some advantages over electromyography (EMG) in certain circumstances, but the use of AMG on the jaw-closing muscles has not been fully tested. The purpose of this study was to examine the relationship between AMG, EMG and force in the masseter muscles of nine healthy male subjects. The AMG was recorded using a piezoelectric crystal microphone and the EMG was recorded simultaneously with surface electrodes. Force was recorded between the anterior teeth with a strain-gauge transducer. Analysis showed that Pearson's correlation coefficient was 0·913 for force/AMG and 0·973 for force/EMG in all subjects, indicating a linear relationship between force, AMG and EMG at the four different force levels tested (25–75% of maximum). It is apparent that AMG may be used as an accurate monitor of masseter muscle force production, although some care is required in the technique.     

Beyond localization: the role of traditional neuropsychological tests in an age of imaging

Rapid advances in structural and functional magnetic resonance imaging (MRI) present two significant challenges to the rationale and role of the traditional neuropsychological assessment in the presurgical evaluation of epilepsy surgery candidates today. The first is a direct challenge to the model of material-specific memory that has underpinned much clinical practice over the last 50 years. The second, more fundamental, challenge goes to the very heart of the lateralizing/localizing approach that has been the cornerstone of clinical neuropsychology practice in epilepsy surgery centers to date. This review examines these challenges and suggests some ways in which the profession might respond and adapt. We conclude that noninvasive neuropsychological assessment remains a critical investigation in the presurgical evaluation of epilepsy surgery patients. Its value stretches beyond the localization of a surgically remediable seizure focus. Once a vital test, other investigations are now superior in this respect in many cases. However, new technologies have enhanced the role of the traditional neuropsychological assessment, which is now able to provide unparalleled insights and predictions into the way in which the underlying pathology, seizures, and proposed surgery shape an individual's profile of cognitive abilities. Detailed neuropsychological feedback enables the patient to make an informed decision, and forms the basis of the tailor made preemptive rehabilitation programs that can be implemented preoperatively, minimizing the most significant morbidity associated with epilepsy surgery today.     

The intriguing case of Christina the Astonishing

Spiritual explanations for epilepsy have existed since antiquity and continue to be prevalent in some communities today. While the vast majority of the unfortunate recipients of this understanding are thought to be possessed by evil forces, a few are deemed to be special vessels for divine communication. Here we present the intriguing case of Christina the Astonishing (1150-1224). Christina appears to be unique in the archives of the religious interpretation of epilepsy in that her seizures were understood to represent her willing submission to demonic torments to provide much needed respite for those in purgatory. Thus she provides an ingenious link between the demonic and divine explanations of the disorder. From a medical perspective, the analysis of contemporary accounts of her afflictions provide compelling evidence of status epilepticus, olfactory auras, and probable frontal lobe epilepsy, with frequent secondary generalization. Even more remarkably, the 13th century accounts of Christina's shame and embarrassment and the social stigma associated with her seizures strike a startling contemporary chord.