IgE, IgE Receptors and Anti-IgE Biologics: Protein Structures and Mechanisms of Action.

The evolution of IgE in mammals added an extra layer of immune protection at body surfaces to provide a rapid and local response against antigens from the environment. The IgE immune response employs potent expulsive and inflammatory forces against local antigen provocation, at the risk of damaging host tissues and causing allergic disease. Two well-known IgE receptors, the high-affinity FcεRI and low-affinity CD23, mediate the activities of IgE. Unlike other known antibody receptors, CD23 also regulates IgE expression, maintaining IgE homeostasis. This mechanism evolved by adapting the function of the complement receptor CD21. Recent insights into the dynamic character of IgE structure, its resultant capacity for allosteric modulation, and the potential for ligand-induced dissociation have revealed previously unappreciated mechanisms for regulation of IgE and IgE complexes. We describe recent research, highlighting structural studies of the IgE network of proteins to analyze the uniquely versatile activities of IgE and anti-IgE biologics.

The correlation between altmetric score and traditional measures of article impact for studies pertaining to spine trauma.

PURPOSE: It is becoming increasingly common for researchers to share scientific literature via social media. Traditional bibliometrics have long been utilized to measure a study's academic impact, but they fail to capture the impact generated through social media sharing. Altmetric Attention Score (AAS) is a weighted count of all the online attention garnered by a study, and it is currently unclear whether a relationship with traditional bibliometrics exists. METHODS: We identified the five highest-rated spine-specific and five highest-rated general orthopedic journals by Scopus CiteScore 2020. We then identified all the spine trauma studies across a 5-year span (2016-2020) within these journals and compared AAS with traditional bibliometrics using Independent t-tests and Pearson's correlational analyses. RESULTS: No statistically significant relationships were identified between AAS and traditional bibliometrics for articles pertaining to spine trauma: Level of Evidence (R = - 0.02, p = 0.34), H-Index Primary Author (R = < - 0.01, p = 0.50), H-Index Senior Author (R = - 0.04, p = 0.24), and Number of Citations (R = 0.01, p = 0.40). The top five articles by AAS include those pertaining to motorcycle injuries (AAS = 687), orthosis in thoracolumbar fractures (AAS = 199), golfing injuries (AAS = 166), smartphone-based teleradiology (AAS = 41), and auto racing injuries (AAS = 39). CONCLUSION: The lack of overlap between these types of metrics suggests that AAS or similar alternative metrics should be used to measure an article's social impact. The social impact of an article should likewise be a factor in determining an article's overall impact along with its academic impact as measured by bibliometrics.

Biomechanical and ergonomic risks associated with cervical musculoskeletal dysfunction amongst surgeons: A systematic review.

INTRODUCTION: Surgeons are at high risk of developing musculoskeletal symptoms due to a range of factors including, maladaptive positioning and surgical ergonomics. Cervical muscle strain and biomechanical load is most prevalent due to repetitive motions and prolonged static neck positioning. This issue is apparent through reports of prevalence between 10 and 74.4% among surgeons. The aim of this systematic review is to provide an objective assessment of the clinical evidence available and a descriptive analysis of the effects of kinematics and surgical ergonomics on the prevalence of surgeons' cervical musculoskeletal pain. METHODS: This is PRISMA-compliant systematic review of clinical studies assessing the prevalence of cervical musculoskeletal dysfunction in surgeons by searching PUBMED and Ovid EMBASE databases from inception to 19th October 2023. Study quality was graded according to the National Institutes of Health study quality assessment tools. RESULTS: A total of 9 studies were included in the final qualitative analysis. The use of loupes, open surgery and excessive neck flexion (>30°) were associated with cervical dysfunction. Comparison of study outcomes was challenging due to heterogeneity within study methods and the paucity of methodological quality. CONCLUSION: The current literature assessing ergonomic and biomechanical factors predisposing surgeons to cervical musculoskeletal dysfunction is insufficient to provide reliable guidance for clinicians. Although the literature identifies factors contributing to work-related cervical dysfunction, few attempt to evaluate interventions for improved surgical ergonomics. An objective assessment of interventions that prompt postural correction with the aim to improve neck pain in surgeon cohorts is warranted.

The efficacy of remote virtual care in comparison to traditional clinical visits for elective orthopaedic patients: A meta-analysis of prospective randomised controlled trials.

INTRODUCTION: The Orthopaedic Trauma Association has recommended limitation of in-person encounters to absolute necessity. One method of ensuring standard patient care within these guidelines is through the implementation of telemedicine. AIMS: To evaluate the efficacy of telemedicine for elective orthopaedic patients in the recovery and/or rehabilitation period. METHODS: A systematic review and meta-analysis of articles in Medline/PubMed and The Cochrane Library databases was performed according to the PRISMA guidelines for prospective randomised controlled trials to compare clinical and symptomatic measures for elective patients managed routinely with remote care compared to those managed with standard in-clinic management. To be included for meta-analysis, parameters must be evaluated in ≥3 studies. RESULTS: Eleven studies were included in the meta-analyses. Both telemedicine and control cohorts were comparable for patient satisfaction (RR, 0.98; 95% CI, 0.90-1.07; I2 = 0%; p = 0.52) and patient retention analysis (RR, 1.25; 95% CI, 0.51-3.06; p = 0.54; I2 = 0%). Similarly, there was no statistical difference appreciated between cohorts for overall Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score (p = 0.30), Timed Up and Go Test (p = 0.40), and Stair Test (p = 0.18). Significant difference did exist for visual analogue scale (VAS) scores (p = 0.02) in favour of in-clinic management. CONCLUSION: Telemedicine will serve an integral aspect of healthcare delivery throughout the current COVID-19 pandemic and beyond in an effort to deliver safe, efficient and time-sensitive care to the orthopaedic patient population. The results of our meta-analyses indicate that virtual consultations are as effective as traditional in-person consultations for the care of elective orthopaedic patients in the recovery and rehabilitation period. However, further studies are needed to evaluate for initial consultations and certain sub-specialties of orthopaedics.

Ontogeny of human IgE-expressing B cells and plasma cells.

BACKGROUND: IgE-expressing (IgE+ ) plasma cells (PCs) provide a continuous source of allergen-specific IgE that is central to allergic responses. The extreme sparsity of IgE+ cells in vivo has confined their study almost entirely to mouse models. OBJECTIVE: To characterize the development pathway of human IgE+ PCs and to determine the ontogeny of human IgE+ PCs. METHODS: To generate human IgE+ cells, we cultured tonsil B cells with IL-4 and anti-CD40. Using FACS and RT-PCR, we examined the phenotype of generated IgE+ cells, the capacity of tonsil B-cell subsets to generate IgE+ PCs and the class switching pathways involved. RESULTS: We have identified three phenotypic stages of IgE+ PC development pathway, namely (i) IgE+ germinal centre (GC)-like B cells, (ii) IgE+ PC-like 'plasmablasts' and (iii) IgE+ PCs. The same phenotypic stages were also observed for IgG1+ cells. Total tonsil B cells give rise to IgE+ PCs by direct and sequential switching, whereas the isolated GC B-cell fraction, the main source of IgE+ PCs, generates IgE+ PCs by sequential switching. PC differentiation of IgE+ cells is accompanied by the down-regulation of surface expression of the short form of membrane IgE (mIgES ), which is homologous to mouse mIgE, and the up-regulation of the long form of mIgE (mIgEL ), which is associated with an enhanced B-cell survival and expressed in humans, but not in mice. CONCLUSION: Generation of IgE+ PCs from tonsil GC B cells occurs mainly via sequential switching from IgG. The mIgEL /mIgES ratio may be implicated in survival of IgE+ B cells during PC differentiation and allergic disease.

Inhibition of allergen-dependent IgE activity by antibodies of the same specificity but different class.

IgG4 purified from patients undergoing specific allergen immunotherapy inhibits the activities of the serum IgE in in vitro assays and is thought to reduce the symptoms of the disease. However, it is not known whether this is related to an intrinsic property of this subclass or only the allergen specificity. We tested the hypothesis that allergen specificity is the critical determinant for this activity using a panel of antibodies with identical specificity but different subclasses. The different antibodies were all able to inhibit the activity of IgE to the same extent. We demonstrate that specificity is the dominant factor determining the ability of an antibody to block allergen-dependent IgE activity.

Surface plasmon resonance: towards an understanding of the mechanisms of biological molecular recognition.

With the introduction of new instruments and improved sensor chip chemistries, surface plasmon resonance (SPR) is finding new applications for molecular interaction studies. Easy access to high-quality kinetic and thermodynamic data for macromolecular binding events is providing insights into the fundamental mechanisms of molecular recognition. Progress is being made to allow larger-scale interaction studies. In addition, combining SPR with other analytical methods is enabling SPR-based analysis of interaction proteomics.

Solution structure and dynamics of the bioactive retroviral M domain from Rous sarcoma virus.

A biologically active construct of the retroviral M domain from the avian Rous sarcoma virus is defined and its solution structure described. This M domain is fully active in budding and infectivity without myristylation. In spite of a sequence homology level that suggests no relationship among M domains and the family of matrix proteins in mammalian retroviruses, the conserved structural elements of a central core allow an M domain sequence motif to be described for all retroviruses. The surface of the M domain has a highly clustered positive patch comprised of sequentially distant residues. An analysis of the backbone dynamics, incorporating rotational anisotropy, is used to estimate the thermodynamics of proposed domain oligomerization.

Validating the GTP-cyclohydrolase 1-feedback regulatory complex as a therapeutic target using biophysical and in vivo approaches.

BACKGROUND AND PURPOSE: 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4 ) is an essential cofactor for nitric oxide biosynthesis. Substantial clinical evidence indicates that intravenous BH4 restores vascular function in patients. Unfortunately, oral BH4 has limited efficacy. Therefore, orally bioavailable pharmacological activators of endogenous BH4 biosynthesis hold significant therapeutic potential. GTP-cyclohydrolase 1 (GCH1), the rate limiting enzyme in BH4 synthesis, forms a protein complex with GCH1 feedback regulatory protein (GFRP). This complex is subject to allosteric feed-forward activation by L-phenylalanine (L-phe). We investigated the effects of L-phe on the biophysical interactions of GCH1 and GFRP and its potential to alter BH4 levels in vivo. EXPERIMENTAL APPROACH: Detailed characterization of GCH1-GFRP protein-protein interactions were performed using surface plasmon resonance (SPR) with or without L-phe. Effects on systemic and vascular BH4 biosynthesis in vivo were investigated following L-phe treatment (100 mg·kg(-1) , p.o.). KEY RESULTS: GCH1 and GFRP proteins interacted in the absence of known ligands or substrate but the presence of L-phe doubled maximal binding and enhanced binding affinity eightfold. Furthermore, the complex displayed very slow association and dissociation rates. In vivo, L-phe challenge induced a sustained elevation of aortic BH4 , an effect absent in GCH1(fl/fl)-Tie2Cre mice. CONCLUSIONS AND IMPLICATIONS: Biophysical data indicate that GCH1 and GFRP are constitutively bound. In vivo, data demonstrated that L-phe elevated vascular BH4 in an endothelial GCH1 dependent manner. Pharmacological agents which mimic the allosteric effects of L-phe on the GCH1-GFRP complex have the potential to elevate endothelial BH4 biosynthesis for numerous cardiovascular disorders.

Bone marrow transplant in adrenoleukodystrophy.

An allogeneic bone marrow transplant (BMT) from a normal HLA identical sibling donor was performed in a 13-year-old boy with rapidly progressive adrenoleukodystrophy (ALD). Engraftment and complete hematologic recovery occurred within 4 weeks, but neurologic deterioration continued. The patient died of an adenovirus infection 141 days after BMT. ALD is characterized by abnormally high plasma levels of very long chain fatty acids (VLCFA) as a result of impaired capacity to degrade them. Ten days after BMT, the white blood cell VLCFA levels and enzyme activity became normal; after 3 months, there was progressive reduction of plasma VLCFA to levels only slightly above normal.

Human papillomavirus DNA in tissues and ocular surface swabs of patients with conjunctival epithelial neoplasia.

DNA from human papillomavirus (HPV) type 16 has been recently identified in conjunctival epithelial dysplasia and carcinoma. In other body sites, HPV 16 is thought to play a role in the development of dysplastic lesions. To further explore the relationship between HPV and conjunctival neoplasia, we examined paraffin-embedded tissue samples from 42 biopsies or excisions from 38 patients whose lesions ranged from mild dysplasia to infiltrating squamous carcinoma of the conjunctiva. We also examined limbal swabs from six patients with dysplasia or carcinoma, five of whom also had tissue samples available for study. HPV 16 DNA was present in 37 (88.1%) tissue samples, including duplicate samples from four patients. Five (83.3%) of six patients who had conjunctival swabs had HPV 16 DNA present in the swabs, including two patients whose lesions had been excised one and eight years before swabs were done. We conclude there is a high prevalence of HPV 16 DNA in conjunctival epithelial neoplasia, suggesting that the development of neoplasia is related somehow to the presence of this virus. However, based on its presence in clinically uninvolved eyes and on the persistence of infection many years after successful eradication of the lesions, HPV apparently does not act alone in the development of conjunctival epithelial neoplasia.

Pulmonary cryptococcosis.

Observation of an unusual pulmonary distribution of cryptococci in a patient at autopsy prompted a review of 36 patients with pulmonary cryptococcosis listed in the autopsy files of The Johns Hopkins Hospital. The patients ranged in age from 2 to 89 years (mean, 49 years), 19 were female, and 18 were black. All but three patients had underlying debilitating diseases, and 23 patients had received steroids and/or chemotherapy. In 25 patients (69 per cent) cryptococcosis was a major factor contributing to death, through pulmonary disease in ten, systemic involvement in seven, and central nervous system disease in eight. In 15 patients (42 per cent) cryptococcosis was diagnosed clinically. Four basic morphologic patterns were observed: 1) Seven patients (19 per cent) had one or more peripheral pulmonary granulomas. In three of these patients the granulomas were apparently quiescent, and no other lesions were found. 2) Nineteen patients (53 per cent) had what has been called granulomatous pneumonia, with intra-alveolar proliferating organisms and varying degrees of inflammatory response, which, when present, ranged from acute inflammation to diffuse intra-alveolar granulomas with giant cells. 3) In seven patients (19 per cent) organisms were present diffusely within alveolar capillaries and interstitial tissues, and reactions ranged from little or no inflammation with numerous organisms to few organisms with miliary granulomas. 4) In three patients (8 per cent) both intra-alveolar and intravascular organisms were present in massive numbers, and the primary route of infection was uncertain. Fatalities from pulmonary and generalized infection occurred in patients in each histologic group. The results show marked variability both in pathologic reaction to cryptococci and in the clinical appreciation and significance of pulmonary cryptococcosis.

Detection of human papillomavirus type 6/11 DNA in conjunctival papillomas by in situ hybridization with radioactive probes.

Twenty-three conjunctival papillomas and 28 conjunctival dysplasias were examined for human papillomavirus (HPV)-DNA sequences by in situ hybridization with nick-translated 35S-labeled HPV probes. Adjacent paraffin sections were hybridized with HPV type 2, 6, 16, and 18 probes at Tm - 17 degrees C. Fifteen tissues, all papillomas, displayed positive hybridization with the HPV-6 probe. Infection with HPV-6 (or the closely related HPV-11) appeared to be responsible for most of the conjunctival papillomas of children and young adults. The presence of genital tract HPV-6 in these lesions suggests that some of the infections were acquired during passage through an infected birth canal. The lack of hybridization in adult conjunctival dysplasias indicates either that HPVs are not associated with this condition or that the probes and the technique utilized were not adequate for demonstration of this association.

Unsuccessful excimer laser phototherapeutic keratectomy. Clinicopathologic correlation.

A 46-year-old man underwent phototherapeutic keratectomy with a 193-nm excimer laser in an attempt to remove a superficial corneal scar that had been present for 36 years. The scar proved to be resistant to ablation with the laser, while relatively normal stroma was easily ablated. Histopathologic examination of the corneal button removed 3 months after excimer laser surgery revealed absence of Bowman's membrane in the area of ablation, superficial stromal disorganization and scarring, raised nodules of collagenous tissue extending into the epithelium, and no calcification within the lesion. Ultrastructural examination was remarkable for irregularly oriented collagen fibers within the scar. The resistance of this lesion to excimer laser ablation appears to have been the consequence of marked differences in rates of ablation between normal stroma and the very long-standing scar.

Demonstration of papillomavirus capsid antigen in human conjunctival neoplasia.

To investigate the association of human papillomavirus with conjunctival neoplasia, we identified 50 resected papillomas from 47 patients. Papillomas were composed of papillary or, less commonly, flat proliferations of predominantly nonkeratinizing squamous epithelium with admixed goblet cells. Koilocytosis was focally present in 30 tumors (60%). Atypia that ranged from mild to severe was present in ten lesions (20%). In addition, we examined specimens of conjunctival dysplasia or carcinoma from 61 patients. The lesions were predominantly flat proliferations of atypical epithelial cells. Twenty biopsies performed for suspected sarcoidosis were used as controls. Papillomavirus capsid antigen was demonstrated using an immunoperoxidase technique in nuclei of mature superficial epithelial cells of 23 papillomas (46%) and five dysplasias or carcinomas (8.2%) but not in the control biopsy specimens. These results suggest that papillomavirus may play a role in the etiology of conjunctival papilloma, dysplasia, and carcinoma.

Genital tract papillomavirus type 6 in recurrent conjunctival papilloma.

An infant boy born of a mother who had condylomata (genital warts) during pregnancy and at delivery developed recurrent conjunctival papillomas and papillomas on the soft palate and the false vocal cords. A conjunctival lesion was first noticed by the mother when the infant was 4 months old and was excised and histologically diagnosed as a papilloma when he was 11 months old. The DNA sequences of genital tract human papillomavirus type 6 (HPV-6) were identified in conjunctival papilloma tissue by Southern transfer hybridization of tissue DNA extracted from a lesion excised at 29 months of age as well as by in situ hybridization of paraffin sections of the diagnostic biopsy specimen obtained at 11 months of age. It is probable that the infant acquired conjunctival infection from the mother, very likely during passage through the infected birth canal.

Human papillomavirus DNA in a recurrent squamous carcinoma of the eyelid.

The polymerase chain reaction (PCR) is a molecular technique that amplifies specific target DNA sequences in vitro to facilitate identification of DNA. We have applied the PCR to a recurrent infiltrating, well-differentiated squamous carcinoma from the right lower eyelid of a 37-year-old woman. With primers specific for human papillomavirus (HPV) type 16 DNA, PCR yielded a single band of amplified DNA product. The product was positive, with a radiolabeled HPV type 16 probe on dot blot analysis. The presence of HPV type 16 viral DNA in this recurrent squamous carcinoma of the eyelid has implications with regard to the possible origin, treatment, and prognosis of the tumor.

Keratocyte loss after corneal deepithelialization in primates and rabbits.

PURPOSE: To evaluate the response of stromal keratocytes to central corneal deepithelialization. METHODS: Rabbits and monkeys underwent unilateral mechanical deepithelialization with a blunt instrument and were killed at intervals ranging from 15 minutes to 24 hours after surgery. Two rabbits underwent unilateral deepithelialization under a fluid bath containing corneal preservation medium. Two rabbits were treated unilaterally with corneal preservation medium topically applied every 15 minutes for 16 hours after epithelial removal. Four rabbits underwent linear keratotomy immediately after deepithelialization of the cornea or on normal unoperated corneas and were killed 1 day (two animals) and 14 days (two animals) after surgery. RESULTS: Deepithelialization resulted in severe ultrastructural changes in keratocytes within 30 minutes after surgery. After 24 hours, the number of keratocytes in the anterior stroma underneath the deepithelialized area had decreased significantly in rabbits (P = .0001) and in monkeys (P = .0007) compared with controls. The wound healing was altered and delayed when the epithelium was not present after keratotomy. The use of storage media during and after deepithelialization minimized the early keratocyte changes and appeared to stimulate reepithelialization. CONCLUSIONS: Removal of corneal epithelium causes loss of superficial stromal keratocytes in rabbits and monkeys. Keratocyte death may results from osmotic changes that alter the corneal wound healing response.