We designed a randomized trial to assess whether the early withdrawal of cyclosporine (CsA) followed by the initiation of everolimus (Evr) monotherapy in de novo liver transplantation (LT) patients would result in superior renal function compared to a CsA-based immunosuppression protocol. All patients were treated with CsA for the first 10 days and then randomized to receive Evr in combination with CsA up to day 30, then either continued on Evr monotherapy (Evr group) or maintained on CsA with/without mycophenolate mofetil (CsA group) in case of chronic kidney disease (CKD). Seventy-eight patients were randomized (Evr n = 52; CsA n = 26). The 1-year freedom from efficacy failure in Evr group was 75% versus 69.2% in CsA group, p = 0.36. There was no statistically significant difference in patient survival between the two groups. Mean modification of diet in renal disease (MDRD) was significantly better in the Evr group at 12 months (87.7 ± 26.1 vs. 59.9 ± 12.6 mL/min; p < 0.001). The incidence of CKD stage ≥3 (estimated glomerular filtration rate <60 mL/min) was higher in the CsA group at 1 year (52.2% vs. 15.4%, p = 0.005). The results indicate that early withdrawal of CsA followed by Evr monotherapy in de novo LT patients is associated with an improvement in renal function, with a similar incidence of rejection and major complications.

Otitis media (OM) is an inflammation of the middle ear associated with infection. Despite appropriate therapy, acute OM (AOM) can progress to chronic suppurative OM (CSOM) associated with ear drum perforation and purulent discharge. The effusion prevents the middle ear ossicles from properly relaying sound vibrations from the ear drum to the oval window of the inner ear, causing conductive hearing loss. In addition, the inflammatory mediators generated during CSOM can penetrate into the inner ear through the round window. This can cause the loss of hair cells in the cochlea, leading to sensorineural hearing loss. Pseudomonas aeruginosa and Staphylococcus aureus are the most predominant pathogens that cause CSOM. Although the pathogenesis of AOM is well studied, very limited research is available in relation to CSOM. With the emergence of antibiotic resistance as well as the ototoxicity of antibiotics and the potential risks of surgery, there is an urgent need to develop effective therapeutic strategies against CSOM. This warrants understanding the role of host immunity in CSOM and how the bacteria evade these potent immune responses. Understanding the molecular mechanisms leading to CSOM will help in designing novel treatment modalities against the disease and hence preventing the hearing loss. IntroductionOtitis media (OM) refers to a group of complex infectious and inflammatory diseases affecting the middle ear (Dickson, 2014). OM in general is very common, as studies show that around 80 % of children should have experienced at least one episode by their third birthday (Teele et al., 1989). OM has been broadly classified into two main types, acute and chronic. Acute OM (AOM) is characterized by the rapid onset of signs of inflammation, specifically bulging and possible perforation of the tympanic membrane, fullness and erythema, as well as symptoms associated with inflammation such as otalgia, irritability and fever (Pukander, 1983;Harkness & Topham, 1998). Despite appropriate antibiotic therapy, AOM may progress to chronic suppurative OM (CSOM) characterized by persistent drainage from the middle ear associated with a perforated ear drum (Wintermeyer & Nahata, 1994;Harkness & Topham, 1998). When examined by otoscope, the middle ear looks red and inflamed with purulent discharge in CSOM patients (Figs 1 and 2). It is one of the most common chronic infectious diseases worldwide especially affecting children (Roland, 2002; Verhoeff et al., 2006). Hearing impairment is one of the most common sequelae of CSOM (Aarhus et al., 2015). The resultant hearing loss can have a negative impact on a child's speech development, education and behaviour (Olatoke et al., 2008; Khairi Md Daud et al., 2010). Mortality due to complications of CSOM is typically higher than other types of OM (Yorgancilar et al., 2013a;Qureishi et al., 2014). Intracranial complications like brain abscess and meningitis are the most common causes of death in CSOM patients (Dubey et al., 2010;Chew et al., 2012;Sun & Sun, 2014).In this article, the rec...

This study hypothesized that decline in sarcoplasmic reticulum (SR) Ca(2+) release and maximal SR-releasable Ca(2+) contributes to decreased specific force with aging. To test it, we recorded electrically evoked maximal isometric specific force followed by 4-chloro-m-cresol (4-CmC)-evoked maximal contracture force in single intact fibers from the mouse flexor digitorum brevis muscle. Significant differences in tetanic, but not in 4-CmC-evoked, contracture forces were recorded in fibers from aging mice as compared to younger mice. Peak intracellular Ca(2+) in response to 4-CmC did not differ significantly. SR Ca(2+) release was recorded in whole-cell patch-clamped fibers in the linescan mode of confocal microscopy using a low-affinity Ca(2+) indicator (Oregon green bapta-5N) with high-intracellular ethylene glycol-bis(alpha-aminoethyl ether)-N,N,N'N'-tetraacetic acid (20 mM). Maximal SR Ca(2+) release, but not voltage dependence, was significantly changed in fibers from old compared to young mice. Increasing the duration of fiber depolarization did not increase the maximal rate of SR Ca(2+) release in fibers from old compared to young mice. Voltage-dependent inactivation of SR Ca(2+) release did not differ significantly between fibers from young and old mice. These findings indicate that alterations in excitation-contraction coupling, but not in maximal SR-releasable Ca(2+), account for the age-dependent decline in intracellular Ca(2+) mobilization and specific force.

Summary Otitis media (OM) is a public health problem in both developed and developing countries. It is the leading cause of hearing loss and represents a significant healthcare burden. In some cases, acute OM progresses to chronic suppurative OM (CSOM), characterized by effusion and discharge, despite antimicrobial therapy. The emergence of antibiotic resistance and potential ototoxicity of antibiotics has created an urgent need to design non-conventional therapeutic strategies against OM based on modern insights into its pathophysiology. In this article, we review the role of innate immunity as it pertains to OM and discuss recent advances in understanding the role of innate immune cells in protecting the middle ear. We also discuss the mechanisms utilized by pathogens to subvert innate immunity and thereby overcome defensive responses. A better knowledge about bacterial virulence and host resistance promises to reveal novel targets to design effective treatment strategies against OM. The identification and characterization of small natural compounds that can boost innate immunity may provide new avenues for the treatment of OM. There is also a need to design novel methods for targeted delivery of these compounds into the middle ear, allowing higher therapeutic doses and minimizing systemic side effects.

Purpose To describe prognostic factors and survival outcomes in patients who underwent orbital exenteration for periocular nonmelanoma cutaneous malignancies. Methods The authors performed an institutional review board-approved retrospective review of all patients who underwent orbital exenteration for nonmelanoma periocular cutaneous malignancies at a tertiary care hospital system over a 10-year period. Patient demographics, tumor, and treatment data were recorded. Survival outcomes included disease-free survival (DFS) and overall survival (OS). Log-rank tests were used to test for difference in survival curves among various potential prognostic indicators, and multivariate analysis was performed using Cox's proportional hazards model. Results Forty-nine patients with an average age of 70.3 years were followed with a median follow-up of 17.5 months. At 2 years the OS was 78% while the DFS was 61%. The mean DFS for basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and sebaceous gland carcinoma (SGC) were 52.6, 39.2 and 28.1 months, respectively. Multivariate analysis demonstrated that only positive final surgical margin was predictive of worse outcome (P = 0.002). Recurrences were most frequent in the first 2 years. Conclusions Despite the relatively more aggressive nature of periocular malignancies that have invaded the orbit, orbital exenteration offers an overall 2-year DFS of 60%. BCC had the greatest mean survival time, however this was not statistically significant. We found worse prognosis with positive final surgical margins and recommend a multidisciplinary surgical approach to achieve complete resection when indicated.