A single dose of AC102 restores hearing in a guinea pig model of noise-induced hearing loss to almost prenoise levels.

Although sudden sensorineural hearing loss (SSNHL) is a serious condition, there are currently no approved drugs for its treatment. Nevertheless, there is a growing understanding that the cochlear pathologies that underlie SSNHL include apoptotic death of sensory outer hair cells (OHCs) as well as loss of ribbon synapses connecting sensory inner hair cells (IHCs) and neurites of the auditory nerve, designated synaptopathy. Noise-induced hearing loss (NIHL) is a common subtype of SSNHL and is widely used to model hearing loss preclinically. Here, we demonstrate that a single interventive application of a small pyridoindole molecule (AC102) into the middle ear restored auditory function almost to prenoise levels in a guinea pig model of NIHL. AC102 prevented noise-triggered loss of OHCs and reduced IHC synaptopathy suggesting a role of AC102 in reconnecting auditory neurons to their sensory target cells. Notably, AC102 exerted its therapeutic properties over a wide frequency range. Such strong improvements in hearing have not previously been demonstrated for other therapeutic agents. In vitro experiments of a neuronal damage model revealed that AC102 protected cells from apoptosis and promoted neurite growth. These effects may be explained by increased production of adenosine triphosphate, indicating improved mitochondrial function, and reduced levels of reactive-oxygen species which prevents the apoptotic processes responsible for OHC death. This action profile of AC102 might be causal for the observed hearing recovery in in vivo models.

Vulvar and perineal verrucous changes complicating hidradenitis suppurativa after wide excision: a case and literature review.

Poorly controlled and long-standing hidradenitis suppurativa (HS) increases the risk of squamous cell carcinoma (SCC). We report a 54-year-old woman with an over 20-year history of HS, who had previously undergone wide perineal excision with secondary intention healing and presented with a painful verrucous vulvar plaque and proximal non-healing perineal wound. The patient had four perineal scouting biopsies performed and excisional biopsy with no evidence of high-grade dysplasia or carcinoma on histology. Chromogenic in situ hybridization was negative for HPV 16 and 18 mRNA; the patient's HIV and HSV PCR were also negative. Our patient was treated with interferon alfa-2b with notable clinical improvement. There is currently no standardized stepwise approach to monitoring verrucous lesions in HS patients with significant risk factors for SCC. Our report highlights a vigilant approach to monitoring. If scouting biopsies are negative, complete testing for high risk HPV strains (HPV 16 and 18) is warranted. If negative, we recommend follow up every 6 months with no further biopsies except if overt clinical changes are observed. We also recommend treatment of verrucous changes to decrease risk of possible malignant conversion. Interferon alfa-2b was effective in decreasing the verrucous lesion burden in our patient and may be considered.

Lactobacillus rescues postnatal neurobehavioral and microglial dysfunction in a model of maternal microbiome dysbiosis.

Increasing reports of pregnancy events leading to maternal microbiome dysbiosis (MMD) show strong correlates with atypical neurodevelopmental outcomes. However, the mechanism(s) driving microbiome-mediated behavioral dysfunction in offspring remain understudied. Here, we demonstrate the presence of a novel gut commensal bacterium strain, Lactobacillus murinus HU-1, was sufficient to rescue behavioral deficits and brain region-specific microglial activationobserved in MMD-reared murine offspring. We furtheridentified a postnatal window of susceptibility that could prevent social impairments with timed maternal administration of the symbiotic bacterium. Moreover, MMD increased expression of microglial senescence genes, Trp53 and Il1ß, and Cx3cr1 protein in the prefrontal cortex, which correlated with dysfunctional modeling of synapses and accompanied dysbiosis-induced microglial activation. MMD male offspring harboring Lactobacillus murinus HU-1 or lacking Cx3cr1 showed amelioration of these effects. The current study describes a new avenue of influence by which maternally transferred Lactobacillus drives proper development of social behavior in the offspring through microglia-specific regulation of Cx3cr1 signaling.

Multi-disciplinary approach to perioperative risk assessment and post-transplant management for liver transplantation in a patient at risk for Brugada syndrome.

Brugada syndrome, an autosomal dominant genetic disorder, is characterised by abnormal electrocardiogram findings and increased risk of ventricular tachyarrhythmias and sudden cardiac death. Our report describes the multi-disciplinary perioperative management of a 28-year-old patient presenting to the Duke Transplant Center with a familial sodium channel gene SCN51 mutation concerning Brugada syndrome. We discuss the preparatory work-up, medication review and appropriate post-surgical follow-up for patients undergoing liver transplant surgery with cardiac monitoring.

Arachidonyl trifluoromethyl ketone is neuroprotective after spinal cord injury.

In spinal cord injury (SCI), neuronal and oligodendroglial loss occurs as a result of the initial trauma and the secondary damage that is triggered by excitotoxicity, free radicals, and inflammation. There is evidence that SCI ellicits increased cytosolic phospholipase A(2) (cPLA(2)) activity. The cleavage of phospholipids by cPLA(2) leads to release of fatty acids, and in particular arachidonic acid (AA), the metabolites of which have been associated with increased inflammation and oxidative stress. The aim of our study was to investigate whether the inhibition of cPLA(2) following SCI leads to tissue protection and an improved functional outcome. Adult rats received compression SCI and 30 min after injury they were treated intravenously with either saline or the cPLA(2) inhibitor arachidonyl trifluoromethyl ketone (AACOCF3) (7.13 mg/kg). The animals were sacrificed at 7 days post-injury and the lesioned tissue was labeled using markers for neurons, oligodendrocytes, and macrophages/activated microglia. We also assessed locomotor recovery using the Basso-Beattie-Bresnahan (BBB) score. The number of surviving neurons and oligodendrocytes was significantly increased in animals treated with the cPLA(2) inhibitor compared to saline controls. The behavioral analysis mirrored the neuroprotective effects and showed that the inhibitor-treated group had better locomotor recovery compared to saline controls. Our results show that AACOCF3 has neuroprotective potential, and support the idea that cPLA(2) is critically involved in acute spinal injury.