A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.

Defects in USH2A cause both isolated retinal disease and Usher syndrome (ie, retinal disease and deafness). To gain insights into isolated/nonsyndromic USH2A retinopathy, we screened USH2A in 186 probands with recessive retinal disease and no hearing complaint in childhood (discovery cohort) and in 84 probands with recessive retinal disease (replication cohort). Detailed phenotyping, including retinal imaging and audiological assessment, was performed in individuals with two likely disease-causing USH2A variants. Further genetic testing, including screening for a deep-intronic disease-causing variant and large deletions/duplications, was performed in those with one likely disease-causing change. Overall, 23 of 186 probands (discovery cohort) were found to harbour two likely disease-causing variants in USH2A. Some of these variants were predominantly associated with nonsyndromic retinal degeneration ('retinal disease-specific'); these included the common c.2276 G>T, p.(Cys759Phe) mutation and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, p.(Arg4192His). An allelic hierarchy was observed in the discovery cohort and confirmed in the replication cohort. In nonsyndromic USH2A disease, retinopathy was consistent with retinitis pigmentosa and the audiological phenotype was variable. USH2A retinopathy is a common cause of nonsyndromic recessive retinal degeneration and has a different mutational spectrum to that observed in Usher syndrome. The following model is proposed: the presence of at least one 'retinal disease-specific' USH2A allele in a patient with USH2A-related disease results in the preservation of normal hearing. Careful genotype-phenotype studies such as this will become increasingly important, especially now that high-throughput sequencing is widely used in the clinical setting.European Journal of Human Genetics advance online publication, 4 February 2015; doi:10.1038/ejhg.2014.283

Roles for Treg expansion and HMGB1 signaling through the TLR1-2-6 axis in determining the magnitude of the antigen-specific immune response to MVA85A

© 2013 Matsumiya et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedA better understanding of the relationships between vaccine, immunogenicity and protection from disease would greatly facilitate vaccine development. Modified vaccinia virus Ankara expressing antigen 85A (MVA85A) is a novel tuberculosis vaccine candidate designed to enhance responses induced by BCG. Antigen-specific interferon-γ (IFN-γ) production is greatly enhanced by MVA85A, however the variability between healthy individuals is extensive. In this study we have sought to characterize the early changes in gene expression in humans following vaccination with MVA85A and relate these to long-term immunogenicity. Two days post-vaccination, MVA85A induces a strong interferon and inflammatory response. Separating volunteers into high and low responders on the basis of T cell responses to 85A peptides measured during the trial, an expansion of circulating CD4+ CD25+ Foxp3+ cells is seen in low but not high responders. Additionally, high levels of Toll-like Receptor (TLR) 1 on day of vaccination are associated with an increased response to antigen 85A. In a classification model, combined expression levels of TLR1, TICAM2 and CD14 on day of vaccination and CTLA4 and IL2Rα two days post-vaccination can classify high and low responders with over 80% accuracy. Furthermore, administering MVA85A in mice with anti-TLR2 antibodies may abrogate high responses, and neutralising antibodies to TLRs 1, 2 or 6 or HMGB1 decrease CXCL2 production during in vitro stimulation with MVA85A. HMGB1 is released into the supernatant following atimulation with MVA85A and we propose this signal may be the trigger activating the TLR pathway. This study suggests an important role for an endogenous ligand in innate sensing of MVA and demonstrates the importance of pattern recognition receptors and regulatory T cell responses in determining the magnitude of the antigen specific immune response to vaccination with MVA85A in humans.This work was funded by the Wellcome Trust. MM has a Wellcome Trust PhD studentship and HM is a Wellcome Trust Senior Fello

Mixed reality in neurosurgery: redefining the paradigm for arteriovenous malformation planning and navigation to improve patient outcomes.

OBJECTIVE: Brain arteriovenous malformations (AVMs) present significant challenges in neurosurgery, requiring detailed planning and execution. In this study, the authors aimed to evaluate the efficacy of mixed reality (MxR), a synergistic application of virtual reality (VR) and augmented reality (AR), in the surgical management of AVMs. METHODS: A retrospective review was conducted on 10 patients who underwent AVM resection between 2021 and 2023. Preoperative planning used patient-specific 360° VR models, while intraoperative guidance used AR markers for targeted disconnection of arterial feeders. Data were analyzed for surgical duration, blood loss, and postoperative outcomes, stratified by Spetzler-Martin (SM) and supplemented Spetzler-Martin (Supp-SM) grades. RESULTS: In 10 patients with cerebral AVMs, MxR significantly facilitated the identification of 21 arterial feeders, including challenging deep feeders. MxR-assisted surgeries demonstrated efficient identification and disconnection of arterial feeders, contributing to precise AVM resection. The mean surgical duration was approximately 5 hours 11 minutes, with a mean intraoperative blood loss of 507.5 ml. Statistically significant variations in surgical duration and blood loss were observed based on SM and supplemented Supp-SM grades. Two patients experienced worsened postoperative neurological deficits, underscoring the inherent risks of AVM surgeries. The marked difference in hospital stays between patients with ruptured and those with unruptured AVMs, particularly for SM grade III, highlights the significant impact of rupture status on postoperative recovery. CONCLUSIONS: In this study, the authors delineated a novel paradigm using MxR for the surgical intervention of AVMs. Using 3D VR for preoperative planning and AR for intraoperative guidance, they achieved unparalleled precision and efficiency in targeting deep arterial feeders. While the results are promising, larger studies are needed to further validate this approach

Endoscopic Endonasal Approach for Complex Macroadenoma with Suprasellar and Retrochiasmatic Extension.

In this video, we describe the technical nuances of an endoscopic endonasal approach (EEA) for a complex macroadenoma with suprasellar and retrochiasmatic extension. The patient is a 51-year-old male with several years\u27 history of progressive visual loss. Neuro-ophthalmology assessment revealed a profound visual loss with homonymous hemianopsia and left optic nerve atrophy. His pituitary hormonal profile was normal. The options for surgical approach included transcranial, endoscopic endonasal, or a combination of both. An EEA was the preferred surgical option, because it allows for early identification of the pituitary gland, and provides access to the suprasellar region including pre- and retrochiasmatic spaces, which facilitates tumor removal while minimizing manipulation of the optic apparatus. While most pituitary adenomas do not require extracapsular subarachnoidal dissection, there are complex adenomas with subarachnoidal invasion and multilobulated morphology, such as the one presented here, that require a combination of internal debulking, extracapsular and subarachnoidal dissection. The technique presented here allows for complete tumor resection, avoiding the risk of postoperative apoplexy of residual adenoma, and facilitates identification of perforating branches and neural structures that require meticulous preservation. Here, we also illustrate the proper management of reconstruction-related complications. Postoperative course was complicated with meningitis with necrotic nasoseptal flap and required surgical debridement, new inferior turbinate flap, fascia lata, lumbar drain, and 6-week antibiotic treatment. Imaging follow-up showed complete removal of tumor. The patient had significant improvement in visual fields and left visual acuity, and no postoperative hormonal dysfunction. The link to the video can be found at: https://youtu.be/9T5b167bVJA

Feasibility of exoscopic keyhole surgery: case series.

Keyhole approaches, performed with the endoscope, microscope, or exoscope, aim to minimize tissue traumatization while maximizing surgical view. The exoscope can provide better ergonomics than the microscope without restricting the space inside of the keyhole, as when using the endoscope. However, a frequently quoted reason for intraoperative exoscope-to-microscope conversion is the absence of sufficient light. In this video, the authors present 4 patients who underwent posterior fossa keyhole surgery without intraoperative conversion. The surgical objective was achieved in all patients without associated morbidity. After adequate adaptation, the exoscope allows sufficient light in the surgical field to perform safe keyhole surgery. The video can be found here: https://stream.cadmore.media/r10.3171/2023.10.FOCVID23116

Delayed spontaneous pneumocephalus in ventriculoperitoneal shunting: two case reports and literature review.

Spontaneous pneumocephalus following cerebrospinal fluid shunt is a rare complication. In most cases, the air enters in the intracranial cavity via a skull base defect. We report 2 cases of delayed tension pneumocephalus, secondary to ventriculoperitoneal shunt, and review the etiopathogenesis, prevention and treatment of this condition

Extended Middle Fossa Approach for Trigeminal Schwannoma Resection.

Trigeminal schwannomas are rare benign tumors, it is second most common intracranial schwannomas after vestibular schwannomas. The management includes not limited to observation, stereotactic radiosurgery/radiotherapy, and/or surgical resection. Tumor size and patient clinical status are the most important factors in management. In this video, we describe the technical nuances of an extended middle fossa approach for large trigeminal schwannoma with cavernous sinus extension resection. A 44-year-old right-handed female with several months\u27 history of progressive right facial paresthesia and pain in the distribution of V3 mainly. On physical examination, she had decreased sensation to light touch over the right V1 to V3 distribution with loss of cornel reflex. The brain MRI showed 3.5 cm bilobed mass extends from the pontine root entry zone to the cavernous sinus. Craniotomy was performed and followed by middle fossa dural peeling, peeling of temporal lobe dura away from the wall of the cavernous sinus, extradurally anterior clinoidectomy, drilling of the petrous apex, coagulation of superior petrosal sinus followed incision of the tentorium up to the tentorial notch with preservation the fourth cranial nerve, and tumor dissected away from V1 and then gradually removed from the superior wall of the cavernous sinus. The technique presented here allows for complete tumor resection, safe navigation through the relative cavernous sinus compartments, and minimizes the possibility of inadvertent injury to the cranial nerves. The postoperative course was uneventful except for right eye incomplete ptosis from the swelling. Her facial pain subsided after the surgery without any extra ocular movement impairment. The link to the video can be found at: https://youtu.be/zxi2XK2R9QU