Role of pyroptosis in hemostasis activation in sepsis.

Sepsis is frequently associated with hemostasis activation and thrombus formation, and systematic hemostatic changes are associated with a higher risk of mortality. The key events underlying hemostasis activation during sepsis are the strong activation of innate immune pathways and the excessive inflammatory response triggered by invading pathogens. Pyroptosis is a proinflammatory form of programmed cell death, that defends against pathogens during sepsis. However, excessive pyroptosis can lead to a dysregulation of host immune responses and organ dysfunction. Recently, pyroptosis has been demonstrated to play a prominent role in hemostasis activation in sepsis. Several studies have demonstrated that pyroptosis participates in the release and coagulation activity of tissue factors. In addition, pyroptosis activates leukocytes, endothelial cells, platelets, which cooperate with the coagulation cascade, leading to hemostasis activation in sepsis. This review article attempts to interpret the molecular and cellular mechanisms of the hemostatic imbalance induced by pyroptosis during sepsis and discusses potential therapeutic strategies.

Diagnostic and therapeutic strategies of acute invasive fungal rhinosinusitis.

Acute invasive fungal rhinosinusitis (AIFR) is a rare disease, but the prognosis is by no means ideal. Pathologically, fungal infection is not only located in the sinus cavity, but also invades the sinus mucosa and bone wall, the surrounding structures and tissues such as the orbit and anterior skull base are often compromised and are accompanied with intracranial and extracranial complications. Despite decades of efforts, acute invasive fungal rhinosinusitis remains a devastating disease, the mortality of the disease continues to hover around 50%. The main impediments to improving the prognosis of acute invasive fungal rhinosinusitis are the difficulties of early diagnosis and the rapid reversal of immune insufficiency. Moreover, aggressive surgery combined with systemic antifungal therapy are significant positive prognostic factors as well. Progress and standardization of AIFR treatment protocols have been limited by the scarcity of the disease and the absence of published randomized studies. Therewith, how to improve the therapeutic outcome and reduce the mortality rate has always been a challenging clinical discussion. We have summarized the relevant case series and literature from the recent years, management with optimal diagnostic and curative strategies are reviewed.

Head and neck radiotherapy causes significant disruptions of cochlear ribbon synapses and consequent sensorineural hearing loss.

PURPOSE: To investigate the possible effects of head and neck radiotherapy on hearing function in mice. METHOD: Adult C57BL/6J mice were irradiated to the head and neck once with cobalt-60 rays at doses of 10 Gy or 20 Gy. Hearing function was estimated by the detection of auditory brainstem response (ABR) thresholds and the suprathreshold function of cochlear was indicated by the peak amplitudes and latencies of wave I. The mice were tested on days 1, 7, 14, and 21 after radiation treatment, and untreated mice in littermates served as controls. The cochlear pre-synaptic ribbons were labeled using an anti-RIBEYE/CtBP2 antibody, and the synaptic vesicle membrane was traced using anti-vesicular glutamate transporter 3 (VGLUT-3) antibody. The number and size of the pre-synaptic ribbons were counted along the cochlear axis from the apex to the base. The expression of VGLUT-3 was measured by the intensity of immunofluorescence. Hematoxylin and eosin (H&E) staining was also performed to evaluate the structural changes in the cochlea. RESULTS: Compared with the controls, mice treated with 10 Gy and 20 Gy doses on days 1, 7, 14, and 21 were found to have significant disruptions in ABR thresholds and amplitudes (p < 0.05). Moreover, mice in the 20 Gy group, compared with the 10 Gy group, showed greater hearing loss and suprathreshold deficits (p < 0.05). Quantitative analysis revealed a decrease in the number and size of CtBP2-positive puncta in both the 10 Gy and 20 Gy groups compared with the controls (p < 0.05); in the 20 Gy group, the number and size of CtBP2-positive puncta were less than those in the 10 Gy group (p < 0.05). We observed a significant disruption in the expression of VGLUT-3 in the group treated with 20 Gy. However, compared with the control group, both immunofluorescence and H&E staining revealed no significant changes in the number of hair cells or the array for the 10 or 20 Gy treatments (p > 0.05). CONCLUSION: Radiation therapy targeting the head and neck can cause sensorineural hearing loss via disruption specific to the cochlear ribbon synapses. To our knowledge, this is the first study to demonstrate that cochlear ribbon synapses may be a subcellular target of radiation-induced hearing loss.

Long-term exposure to low-intensity environmental noise aggravates age-related hearing loss via disruption of cochlear ribbon synapses.

Noise pollution is a major public hazard. Previous studies have shown that environmental noise affects the reorganization of the auditory cortex and leads to behavioral abnormality; however, the effects of long-term environmental noise exposure on the inner ear and hearing remain to be elucidated. In this study, we simulated environmental noise with a long-term 70 dB sound pressure level "white" noise, observed its effect on the inner ears of C57BL/6J mice, and developed an in vitro model for mechanistic studies. We found that environmental noise increased the hearing threshold, decreased the auditory response amplitude, and aggravated the range and extent of age-related hearing loss (ARHL), especially in the intermediate frequency band in mice. Cochlear ribbon synapse is the primary site of inner ear injury caused by environmental noise. We also verified, through an in vitro simulation of the excitatory toxicity of glutamate and aging effects, that the activation of NLRP3 inflammasome plays a vital role in the cochlear ribbon synaptic damage. Our results show that long-term exposure to low-intensity environmental noise can lead to hearing loss via the disruption of ribbon synapses, which is caused by an inflammatory reaction. Additionally, environmental noise can further aggravate the progression of ARHL. This study expounded the pathogenesis of the inner ear damage caused by environmental noise exposure and provides a new direction for the prevention and treatment of hearing loss.

Repeated Moderate Sound Exposure Causes Accumulated Trauma to Cochlear Ribbon Synapses in Mice.

Repeated induction of a temporary threshold shift (TTS) may result in a permanent threshold shift (PTS) and is thought to be associated with early onset of age-related hearing loss (ARHL). The possibility that a PTS might be induced by administration of repeated TTS-inducing noise exposures (NEs) over a short period during early adulthood has not been formally investigated. We aimed to investigate possible cumulative acoustic overstimulation effects that permanently shift the auditory threshold. Young adult C57BL/6J mice were exposed twice to moderate white noise in an experimental design that minimized the effects of aging. The first exposure resulted in a reversible noise-induced hearing loss (NIHL) measured as recoverable alterations in auditory brainstem response (ABR) thresholds, waveform amplitudes, and numbers of ribbon synapses. The second NE with the same parameters caused persistent threshold shifts, wave I amplitude reductions, wave IV/I ratio enhancements, and synaptic losses, even though recovery time sufficient for a TTS had been provided. The pattern of PTS resembled NIHL since the observed impairments tonotopically followed the power spectrum of the noise insult, rather than ARHL, which distributes at higher frequencies. No significant changes were observed in the control group as the mice aged. To conclude, our results demonstrate a cumulative effect of repetitive TTS-inducing NE on hearing function and synaptic plasticity that does not cause premature ARHL, thereby providing insight into the pathophysiological mechanisms underlying NIHL and ARHL.

[Research of cochlear coiling pattern and orientation in general population by CT 3D reconstruction].

OBJECTIVE: To perform morphometric analysis of bilateral cochleae in all subjects based on computed 3-dimensional reconstruction tomographic data and assist the surgeon in diagnosing the inner ear abnormality or surgical strategies. METHOD: Two hundred normal developed cochleae from 100 patients were divided into 5 groups according to age. Morphometric analysis of bilateral cochleae was performed in all subjects by 3D reconstructions and 2D multiplanar reformation. The length and width of the cochlear base, the length within the cochlear base, the height of the cochlea, the angle between the first and second turn of the cochlea, and the cochlear orientation within the cranial base were measured and compared in different age, sex and bilateral groups. RESULT: The length of the cochlear base was (8.56 +/- 0.52)mm, the width was (6.63 +/- 0.56)mm, the length within the cochlear base was (7.33 +/- 10.56)mm, the height of the cochlea was (3.76 +/- 0.28)mm, and the angle between the first and second turn of the cochlea was (15.82 +/- 2.78)degrees. All index above did not change significantly in different aging, sex or side (P > 0. 05). Variability in the angle between the first and second turn of the cochlea was considerable, and a smaller angle (from the midsagittal line) was showed in the older age groups than the younger groups (P < 0.05). CONCLUSION: 3D and 2D volume rendering enables us to evaluate the features of cochlear morphology and orientation that may assist the surgeon in diagnosing the inner ear abnormality or surgical strategies.