The bacterial lysate OM-85 engages Toll-like receptors 2 and 4 triggering an immunomodulatory gene signature in human myeloid cells.

OM-85 is a bacterial lysate used in clinical practice to reduce duration and frequency of recurrent respiratory tract infections. Whereas knowledge of its regulatory effects in vivo has substantially advanced, the mechanisms of OM-85 sensing remain inadequately addressed. Here, we show that the immune response to OM-85 in the mouse is largely mediated by myeloid immune cells through Toll-like receptor (TLR) 4 in vitro and in vivo. Instead, in human immune cells, TLR2 and TLR4 orchestrate the response to OM-85, which binds to both receptors as shown by surface plasmon resonance assay. Ribonucleic acid-sequencing analyses of human monocyte-derived dendritic cells reveal that OM-85 triggers a pro-inflammatory signature and a unique gene set, which is not induced by canonical agonists of TLR2 or TLR4 and comprises tolerogenic genes. A largely overlapping TLR2/4-dependent gene signature was observed in individual subsets of primary human airway myeloid cells, highlighting the robust effects of OM-85. Collectively, our results suggest caution should be taken when relating murine studies on bacterial lysates to humans. Furthermore, our data shed light on how a standardized bacterial lysate shapes the response through TLR2 and TLR4, which are crucial for immune response, trained immunity, and tolerance.

Myc controls NK cell development, IL-15-driven expansion, and translational machinery.

MYC is a pleiotropic transcription factor involved in cancer, cell proliferation, and metabolism. Its regulation and function in NK cells, which are innate cytotoxic lymphocytes important to control viral infections and cancer, remain poorly defined. Here, we show that mice deficient for Myc in NK cells presented a severe reduction in these lymphocytes. Myc was required for NK cell development and expansion in response to the key cytokine IL-15, which induced Myc through transcriptional and posttranslational mechanisms. Mechanistically, Myc ablation in vivo largely impacted NK cells' ribosomagenesis, reducing their translation and expansion capacities. Similar results were obtained by inhibiting MYC in human NK cells. Impairing translation by pharmacological intervention phenocopied the consequences of deleting or blocking MYC in vitro. Notably, mice lacking Myc in NK cells exhibited defective anticancer immunity, which reflected their decreased numbers of mature NK cells exerting suboptimal cytotoxic functions. These results indicate that MYC is a central node in NK cells, connecting IL-15 to translational fitness, expansion, and anticancer immunity.

Concomitant deletion of Ptpn6 and Ptpn11 in T cells fails to improve anticancer responses.

Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Blockade of PD-1 leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase PTPN11 (known as SHP-2) is essential for PD-1 signaling in T cells, suggesting functional redundancy with the homologous phosphatase PTPN6 (SHP-1). Therefore, we investigated the effect of concomitant Ptpn6 and Ptpn11 deletion in T cells on their ability to mount antitumour responses. In vivo data show that neither sustained nor acute Ptpn6/11 deletion improves T cell-mediated tumor control. Sustained loss of Ptpn6/11 also impairs the therapeutic effects of anti-PD1 treatment. In vitro results show that Ptpn6/11-deleted CD8+ T cells exhibit impaired expansion due to a survival defect and proteomics analyses reveal substantial alterations, including in apoptosis-related pathways. These data indicate that concomitant ablation of Ptpn6/11 in polyclonal T cells fails to improve their anticancer properties, implying that caution shall be taken when considering their inhibition for immunotherapeutic approaches.

Do patients report quality of life improvements after fitting of their unilateral bone conducting hearing implant?

OBJECTIVE: The audiological benefits of a bone conducting hearing implant are well documented; however, there is a paucity of literature comparing pre- and post-operative quality of life benefits. This study assessed the quality of life status before and after the device is implanted. METHODS: A prospective study was conducted of all adult bone conducting hearing implants inserted in a teaching hospital between 2012 and 2017. All patients completed the Glasgow Health Status Inventory, a validated quality of life questionnaire, before and three to six months after implantation. RESULTS: Sixty-two patients received a unilateral bone conducting hearing implant. All scores except the social score improved post-operatively. The paired t-test showed that the differences in the means for the Glasgow Health Status Inventory total, general and physical scores were statistically significant at the 5 per cent level (p < 0.0001). CONCLUSION: This study, one of the few to assess quality of life pre- and post-implantation, showed a vast improvement in patients' perceived quality of life from the pre- to the post-operative phase.

Distinct Antiviral Properties of Two Different Bacterial Lysates.

Oral bacterial lysates (OBLs) can reduce the frequency and severity of recurrent respiratory tract infections in children from viral and bacterial origins. OBL-induced early innate immune reaction was already shown, but the specific features of different OBLs have never been studied and compared. A study was conducted to assess in vitro the protective effects on rhinovirus- (RV-) infected human bronchial epithelial cells (BECs) of two slightly different OBLs: OM-85 and Pulmonarom. Furthermore, since immune cells represent the key arm for antiviral defence, the capacity of these OBLs to induce selected cytokine production in mouse bone marrow-derived DCs (BMDCs) was also evaluated. Although different OBLs may share some mechanisms to protect host cells from virus infection, some product-specific antimicrobial activities were observed on RV-infected human BECs and mouse BMDCs. These results are consistent with a product-specific response possibly triggered by different pathogen-associated molecular patterns (PAMPs) contained in OBLs.

NLRC5 promotes transcription of BTN3A1-3 genes and Vγ9Vδ2 T cell-mediated killing.

BTN3A molecules-BTN3A1 in particular-emerged as important mediators of Vγ9Vδ2 T cell activation by phosphoantigens. These metabolites can originate from infections, e.g. with Mycobacterium tuberculosis, or by alterations in cellular metabolism. Despite the growing interest in the BTN3A genes and their high expression in immune cells and various cancers, little is known about their transcriptional regulation. Here we show that these genes are induced by NLRC5, a regulator of MHC class I gene transcription, through an atypical regulatory motif found in their promoters. Accordingly, a robust correlation between NLRC5 and BTN3A gene expression was found in healthy, in M. tuberculosis-infected donors' blood cells, and in primary tumors. Moreover, forcing NLRC5 expression promoted Vγ9Vδ2 T-cell-mediated killing of tumor cells in a BTN3A-dependent manner. Altogether, these findings indicate that NLRC5 regulates the expression of BTN3A genes and hence open opportunities to modulate antimicrobial and anticancer immunity.

C5a Regulates IL-1ß Production and Leukocyte Recruitment in a Murine Model of Monosodium Urate Crystal-Induced Peritonitis.

Gouty arthritis results from the generation of monosodium urate (MSU) crystals within joints. These MSU crystals elicit acute inflammation characterized by massive infiltration of neutrophils and monocytes that are mobilized by the pro-inflammatory cytokine IL-1ß. MSU crystals also activate the complement system, which regulates the inflammatory response; however, it is unclear whether or how MSU-mediated complement activation is linked to IL-1ß release in vivo, and the various roles that might be played by individual components of the complement cascade. Here we show that exposure to MSU crystals in vivo triggers the complement cascade, leading to the generation of the biologically active complement proteins C3a and C5a. C5a, but not C3a, potentiated IL-1ß and IL-1α release from LPS-primed MSU-exposed peritoneal macrophages and human monocytic cells in vitro; while in vivo MSU-induced C5a mediated murine neutrophil recruitment as well as IL-1ß production at the site of inflammation. These effects were significantly ameliorated by treatment of mice with a C5a receptor antagonist. Mechanistic studies revealed that C5a most likely increased NLRP3 inflammasome activation via production of reactive oxygen species (ROS), and not through increased transcription of inflammasome components. Therefore we conclude that C5a generated upon MSU-induced complement activation increases neutrophil recruitment in vivo by promoting IL-1 production via the generation of ROS, which activate the NLRP3 inflammasome. Identification of the C5a receptor as a key determinant of IL-1-mediated recruitment of inflammatory cells provides a novel potential target for therapeutic intervention to mitigate gouty arthritis.

Neoplastic leptomeningeal disease masquerading as central serous retinopathy. A case report.

A 69-year-old man became aware of people's speech being out of synch with their lip movements alongside persistent headaches, both of which progressively worsened. A few weeks later, he developed progressive and painless visual loss in one eye. Initial neurological evaluation, inflammatory markers and head computed tomography scan were normal. Ophthalmological examination and OCT scan revealed right macular subretinal fluid with choroidal indentation, which prompted urgent further investigations including head MRI revealing extensive leptomeningeal disease. The patient continued to deteriorate and deceased shortly afterwards. This is the first reported case of neoplastic leptomeningeal disease presenting with loss of vision due to choroidal metastasis with localised exudative retinal detachment. Diagnosing neoplastic leptomeningeal disease requires a high index of suspicion from the treating physician. Symptoms may be nonspecific and/or subtle. Combining cerebrospinal fluid cytology from lumbar puncture with contrast-enhanced magnetic resonance imaging of the brain is considered the optimal diagnostic approach.

Unilateral blindness secondary to acute sphenoid sinusitis.

OBJECTIVES: To highlight a rare scenario where a delay in diagnosis caused unilateral blindness. CASE REPORT: A 45-year-old Aboriginal woman with a history of non-Hodgkin's lymphoma presented with a severe left-sided headache, pyrexia and positive blood cultures. Following admission, the patient rapidly developed unilateral blindness, but did not inform her physician until 21 hours after onset. High-resolution CT scanning of the sinuses showed erosion of the bony covering of the optic nerve. Sinus surgery was performed. RESULTS: Despite the discovery of pus under considerable pressure, and clearing the sphenoid sinus of pus and debris, vision was not restored, even at 2-month follow-up. CONCLUSIONS: Two pathological processes are postulated here: that erosion of the bony optic canal allowed the optic nerve to be exposed, allowing the ensuing sinusitis to cause irreversible nerve ischemia, and immunosuppression meant the patient's immune response was inadequate to cope with the sinusitis, with devastating effects.

Anterior fracture dislocation of the odontoid peg in ankylosing spondylitis as a cause for rhinolalia clausa: a case study.

We present an unusual cause of rhinolalia clausa secondary to an oropharyngeal mass. A 69-year-old male presented to the otorhinolaryngology clinic with a one year history of a 'plummy' voice. He had a longstanding history of severe ankylosing spondylitis. Examination revealed an obvious hyponasal voice and a smooth hard mass in the midline of the posterior nasopharyngeal and oropharyngeal walls. Subsequent computed tomography scans and lateral plain neck X-ray showed a fracture dislocation of the odontoid peg, secondary to ankylosing spondylitis, which had eroded through the body of the C1 vertebra to lie anteriorly, resulting in the aforementioned impression into the pharyngeal mucosa. The radiological images, the role of the nasal airways in phonation and the causes of hyponasal speech are discussed.

Silver nitrate: histological effects of cautery on epithelial surfaces with varying contact times.

Silver nitrate is used extensively in rhinological practice for the treatment of recurrent epistaxis. There are currently no recommendations in the literature regarding the optimum application time of this chemical for effective treatment. We assessed the histological effects of silver nitrate on mucosal tissue at varying contact times and made recommendations based on our findings. Silver nitrate was applied at predetermined contact times to tonsillar mucosa, immediately before tonsillectomy in subjects undergoing routine surgery. The cauterized areas were subsequently analysed histologically. The depth of tissue penetration by the silver nitrate was measured. The means for 5, 10 and 20 s were 0.44, 0.30 and 0.38, respectively, P = 0.3. Overall, there was no deeper penetration of the tissues with contact times over 5 s. We conclude that it is not necessary to apply silver nitrate for greater than 5 s to achieve maximal tissue penetration.

Use of a portable spirometer for studies on the nasal cycle.

Studies based on the nasal cycle are difficult because multiple measurements of nasal patency need to be made over many hours. There is a great need for a simple portable instrument that can be used away from the clinical laboratory for studies on the nasal cycle. Our aim was to investigate the usefulness of a small portable spirometer in studying the nasal cycle. The Mir Spirobank spirometer was fitted with a nasal adapter to measure the volume of air expired from each nasal passage during a slow vital capacity (VC). The spirometer was used to measure the fractions of the slow VC volume of air expired through the right and left nasal passage in turn. Hourly measurements were made over a 5-hour period in six healthy volunteers. The spirometry measurements of the volume of air expired from each nasal passage were compared with nasal conductance of each nasal passage (airflow at 75 Pa) obtained by posterior rhinomanometry. The spirometer was found easy to use by both the investigator and the patients. Simple regression analysis of the spirometer and rhinomanometer measures of airflow partitioning found a correlation coefficient of r = 0.827 (p < 0.0001: n = 36). These results indicate that the partitioning of nasal expired volume measured by spirometry is directly comparable with partitioning of nasal airflow obtained with rhinomanometry. Spirometry has considerable advantages over rhinomanometry for studies on the nasal cycle because of portability and ease of use.

Sensorineural hearing loss in linear IgA disease.

A 23-year-old female with progressive sensorineural hearing loss developed widespread blistering eruptions while under evaluation for the hearing loss. The lesions showed findings characteristic of linear IgA disease (LAD) on histochemical studies. Linear IgA disease is a dapsone responsive autoimmune subepidermal blistering disease characterised by linear IgA deposits in the basement membrane zone. The complete spectrum of this systemic disease is still not clear and this is the first report of association between LAD and sensorineural deafness.

Post-tonsillectomy patient care in the community.

Tonsillectomy is a frequently performed surgical procedure. Problems arising in the early postoperative period will have an important impact on community and hospital resources. We determined the type of problems that occur and the way these problems are managed. We monitored 203 patients undergoing routine tonsillectomy by a postoperative telephone survey and contacted their general practitioners, 164 in all. We found 46% of the patients experienced problems post-discharge which led to early contact with a doctor. Infection was identified in 26% and secondary haemorrhage in 11%. Common symptoms associated with the prescribing of antibiotics were sore throat (74%) and secondary haemorrhage (41%). Each GP saw, on average, 2.4 post-tonsillectomy patients per annum. The diagnosis of post-tonsillectomy infection is difficult. This was reflected in the wide variation of clinical features used to diagnose post-tonsillectomy infection by doctors. The vast majority (95%) of GPs expressed a desire for a framework for treating post-tonsillectomy complications.