The Rac-GEF Tiam1 controls integrin-dependent neutrophil responses

Rac GTPases are required for neutrophil adhesion and migration, and for the neutrophil effector responses that kill pathogens. These Rac-dependent functions are impaired when neutrophils lack the activators of Rac, Rac-GEFs from the Prex, Vav, and Dock families. In this study, we demonstrate that Tiam1 is also expressed in neutrophils, governing focal complexes, actin cytoskeletal dynamics, polarisation, and migration, in a manner depending on the integrin ligand to which the cells adhere. Tiam1 is dispensable for the generation of reactive oxygen species but mediates degranulation and NETs release in adherent neutrophils, as well as the killing of bacteria. In vivo, Tiam1 is required for neutrophil recruitment during aseptic peritonitis and for the clearance of Streptococcus pneumoniae during pulmonary infection. However, Tiam1 functions differently to other Rac-GEFs. Instead of promoting neutrophil adhesion to ICAM1 and stimulating β2 integrin activity as could be expected, Tiam1 restricts these processes. In accordance with these paradoxical inhibitory roles, Tiam1 limits the fMLP-stimulated activation of Rac1 and Rac2 in adherent neutrophils, rather than activating Rac as expected. Tiam1 promotes the expression of several regulators of small GTPases and cytoskeletal dynamics, including αPix, Psd4, Rasa3, and Tiam2. It also controls the association of Rasa3, and potentially αPix, Git2, Psd4, and 14-3-3ζ/δ, with Rac. We propose these latter roles of Tiam1 underlie its effects on Rac and β2 integrin activity and on cell responses. Hence, Tiam1 is a novel regulator of Rac-dependent neutrophil responses that functions differently to other known neutrophil Rac-GEFs

An Osteoma of the Middle Ear Presenting with the Tullio Phenomenon

The Tullio phenomenon is an extremely rare condition in which loud noise induces a brisk vestibular response. Osteomas of the middle ear cleft are also uncommon. We report a patient with an osteoma of the middle ear cleft that became symptomatic with progressive facial palsy and mixed hearing loss. The onset was heralded by the Tullio phenomenon, which she had experienced for 10 years. The differential diagnosis of the Tullio phenomenon and the management of middle ear osteomas are discussed

The Effect of Observation versus Microsurgical Excision on Quality of Life in Unilateral Vestibular Schwannoma: A Prospective Study

With the emergence of three effective management options for vestibular schwannoma and the drastic reduction in mortality rate, the last two decades have seen increasing attention being paid to health-related quality of life. The vast majority of quality of life studies have been retrospective. We prospectively assessed quality of life of vestibular schwannoma patients before and after conservative or microsurgical management. We performed a prospective observational study conducted at a tertiary referral center between October 2001 and October 2003. Patients were divided into two groups: conservative management and microsurgery. Quality of life was assessed using the Medical Outcome Study 36-Item Short Form (SF-36) and Glasgow Benefit Inventory (GBI). The questionnaires were administered at initial assessment, 1 month, 3 months, and 6 months in both groups. Thirty-three patients completed the study, 18 in the conservative group and 15 in the microsurgical group. One month after microsurgery, SF-36 scores were significantly reduced within three of eight domains; however, 3 months after microsurgery, no significant difference existed in patients' scores on any of the SF-36 domains compared with preoperatively, and at 6 months there was a significant improvement in one domain compared with preoperatively. There was no significant difference in overall quality of life alteration (GBI total score) between microsurgery and conservative management. The improved quality of life of patients 6 months after microsurgery (relative to preoperatively, and in comparison with an age- and sex- matched population) is a new finding that has not been previously documented in the literature

The GPCR adaptor protein norbin suppresses the neutrophil-mediated immunity of mice to pneumococcal infection

Streptococcal pneumonia is a worldwide health problem that kills 2 million people each year, particularly young children, the elderly, and immunosuppressed individuals. Alveolar macrophages and neutrophils provide the early innate immune response to clear pneumococcus from infected lungs. However, the level of neutrophil involvement is context dependent, both in humans and in mouse models of the disease, influenced by factors such as bacterial load, age, and coinfections. Here, we show that the G protein coupled receptor (GPCR) adaptor protein norbin (neurochondrin, NCDN), which was hitherto known as a regulator of neuronal function, is a suppressor of neutrophilmediated innate immunity. Myeloid norbin deficiency improved the immunity of mice to pneumococcal infection by increasing the involvement of neutrophils in clearing the bacteria, without affecting neutrophil recruitment or causing autoinflammation. It also improved immunity during Escherichia coli induced septic peritonitis. It increased the responsiveness of neutrophils to a range of stimuli, promoting their ability to kill bacteria in a reactive oxygen species dependent manner, enhancing degranulation, phagocytosis, and the production of reactive oxygen species and neutrophil extracellular traps, raising the cell surface levels of selected GPCRs, and increasing GPCR-dependent Rac and Erk signaling. The Rac guanine-nucleotide exchange factor Prex1, a known effector of norbin, was dispensable for most of these effects, which suggested that norbin controls additional downstream targets. We identified the Rac guanine-nucleotide exchange factor Vav as one of these effectors. In summary, our study presents the GPCR adaptor protein norbin as an immune suppressor that limits the ability of neutrophils to clear bacterial infections