Alginate oligosaccharides enhance the antifungal activity of nystatin against candidal biofilms.

Background: The increasing prevalence of invasive fungal infections in immuno-compromised patients is a considerable cause of morbidity and mortality. With the rapid emergence of antifungal resistance and an inadequate pipeline of new therapies, novel treatment strategies are now urgently required. Methods: The antifungal activity of the alginate oligosaccharide OligoG in conjunction with nystatin was tested against a range of Candida spp. (C. albicans, C. glabrata, C. parapsilosis, C. auris, C. tropicalis and C. dubliniensis), in both planktonic and biofilm assays, to determine its potential clinical utility to enhance the treatment of candidal infections. The effect of OligoG (0-6%) ± nystatin on Candida spp. was examined in minimum inhibitory concentration (MIC) and growth curve assays. Antifungal effects of OligoG and nystatin treatment on biofilm formation and disruption were characterized using confocal laser scanning microscopy (CLSM), scanning electron microscopy (SEM) and ATP cellular viability assays. Effects on the cell membrane were determined using permeability assays and transmission electron microscopy (TEM). Results: MIC and growth curve assays demonstrated the synergistic effects of OligoG (0-6%) with nystatin, resulting in an up to 32-fold reduction in MIC, and a significant reduction in the growth of C. parapsilosis and C. auris (minimum significant difference = 0.2 and 0.12 respectively). CLSM and SEM imaging demonstrated that the combination treatment of OligoG (4%) with nystatin (1 µg/ml) resulted in significant inhibition of candidal biofilm formation on glass and clinical grade silicone surfaces (p < 0.001), with increased cell death (p < 0.0001). The ATP biofilm disruption assay demonstrated a significant reduction in cell viability with OligoG (4%) alone and the combined OligoG/nystatin (MIC value) treatment (p < 0.04) for all Candida strains tested. TEM studies revealed the combined OligoG/nystatin treatment induced structural reorganization of the Candida cell membrane, with increased permeability when compared to the untreated control (p < 0.001). Conclusions: Antimicrobial synergy between OligoG and nystatin against Candida spp. highlights the potential utility of this combination therapy in the prevention and topical treatment of candidal biofilm infections, to overcome the inherent tolerance of biofilm structures to antifungal agents.

Hearing Loss in Adults With Alström Syndrome-Experience From the UK National Alström Service.

OBJECTIVE: To characterize the patterns of hearing loss and methods of hearing rehabilitation in the UK national cohort of adults with Alström syndrome. STUDY DESIGN: Retrospective review of electronic patient records. SETTING: UK National multi-disciplinary team (MDT) Alström service held at the Queen Elizabeth Hospital, Birmingham. PATIENTS: Forty one adult patients with a diagnosis of Alström syndrome, confirmed via ALMS1 gene sequencing, are under ongoing review within the UK National MDT Alström service. MAIN OUTCOME MEASURES: Magnitude and type of hearing loss were analyzed using patients' audiometric data. Deterioration of hearing was calculated using serial pure tone audiograms. Methods of hearing rehabilitation used by patients and potential candidacy for cochlear implantation were analyzed. RESULTS: Of 34 patients with available audiograms, all had sensorineural hearing loss (SNHL). Dual sensory (visual and hearing) loss was present in 32/34 (94%) patients. Hearing deteriorated with advancing age, at 1.23 dB/yr. Severe- profound SNHL was present in 9/34 (26%) cases. Air conduction hearing aids were used in 27/34 (79%) cases, and cochlear implants in 2/34 (5%). CONCLUSIONS: Alström syndrome is an ultra-rare genetic disorder with progressive, debilitating multi-system manifestations, including SNHL. The UK National MDT Alström service represents one of the largest reported adult cohorts in the world. SNHL in this group was ubiquitous, showing a rapid decline in hearing with age. Annual audiometric assessment to enable early diagnosis of hearing loss and optimum rehabilitation are paramount to minimize the impact of hearing loss in this condition.

Lessons learnt from a case of extracorporeal shockwave lithotripsy for a residual gallbladder stone.

INTRODUCTION: Extracorporeal shockwave lithotripsy (ECSWL) for gallstones is rarely used due to high recurrence rates, but has been reported to be effective in some circumstances. PRESENTATION OF CASE: We describe a case of a failed attempt at laparoscopic cholecystectomy due to gallbladder contraction and complete obliteration of Calot's triangle. Cholecystotomy was performed to remove all visible stones, and completed by a subtotal cholecystectomy and closure of the gallbladder remnant. The patient remained symptomatic due to a residual stone in the Hartmann's pouch. ECSWL was attempted to fragment the stone; however, follow-up imaging showed persistence of the calculus. DISCUSSION: Literature review shows that ECSWL for multiple gallbladder stones has a low success rate. Even if a stone is successfully fragmented, a diseased gallbladder remnant seems incapable of expelling the fragments. Without completion endoscopic clearance, therefore, the treatment is considered incomplete. CONCLUSION: Our case suggests that ECSWL is ineffective in management of residual gallbladder stones after failed cholecystectomy.

Atypical presentation of Bezold's and Citelli's abscesses, with recollection following an incomplete postoperative course of antibiotics.

Bezold's and Citelli's abscesses are rare complications of otitis media. We present a case of a 44-year-old Eastern European man, with a history of recurrent otitis media, who was admitted to hospital with mastoiditis and initially treated with antibiotics. Despite clinical improvement, a CT scan showed mastoiditis with Bezold's and Citelli's abscesses. The patient underwent a myringotomy and grommet insertion, in addition to a cortical mastoidectomy and curettage of the neck abscesses. After a good recovery, he was discharged home. However, likely due to the language barrier, he did not complete a course of antibiotics as prescribed, and the abscess re-collected, necessitating a re-admission and re-operation. This report illustrates the importance of considering rare features of a common disease in the differential, and of communication in ensuring compliance.

Impact on clinical and cost outcomes of a centralized approach to acute stroke care in London: a comparative effectiveness before and after model.

BACKGROUND: In July 2010 a new multiple hub-and-spoke model for acute stroke care was implemented across the whole of London, UK, with continuous specialist care during the first 72 hours provided at 8 hyper-acute stroke units (HASUs) compared to the previous model of 30 local hospitals receiving acute stroke patients. We investigated differences in clinical outcomes and costs between the new and old models. METHODS: We compared outcomes and costs 'before' (July 2007-July 2008) vs. 'after' (July 2010-June 2011) the introduction of the new model, adjusted for patient characteristics and national time trends in mortality and length of stay. We constructed 90-day and 10-year decision analytic models using data from population based stroke registers, audits and published sources. Mortality and length of stay were modelled using survival analysis. FINDINGS: In a pooled sample of 307 patients 'before' and 3156 patients 'after', survival improved in the 'after' period (age adjusted hazard ratio 0.54; 95% CI 0.41-0.72). The predicted survival rates at 90 days in the deterministic model adjusted for national trends were 87.2% 'before' % (95% CI 86.7%-87.7%) and 88.7% 'after' (95% CI 88.6%-88.8%); a relative reduction in deaths of 12% (95% CI 8%-16%). Based on a cohort of 6,438 stroke patients, the model produces a total cost saving of £5.2 million per year at 90 days (95% CI £4.9-£5.5 million; £811 per patient). CONCLUSION: A centralized model for acute stroke care across an entire metropolitan city appears to have reduced mortality for a reduced cost per patient, predominately as a result of reduced hospital length of stay.

Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates.

The complement system is an essential component of the innate and acquired immune system, and consists of a series of proteolytic cascades that are initiated by the presence of microorganisms. In health, activation of complement is precisely controlled through membrane-bound and soluble plasma-regulatory proteins including complement factor H (fH; ref. 2), a 155 kDa protein composed of 20 domains (termed complement control protein repeats). Many pathogens have evolved the ability to avoid immune-killing by recruiting host complement regulators and several pathogens have adapted to avoid complement-mediated killing by sequestering fH to their surface. Here we present the structure of a complement regulator in complex with its pathogen surface-protein ligand. This reveals how the important human pathogen Neisseria meningitidis subverts immune responses by mimicking the host, using protein instead of charged-carbohydrate chemistry to recruit the host complement regulator, fH. The structure also indicates the molecular basis of the host-specificity of the interaction between fH and the meningococcus, and informs attempts to develop novel therapeutics and vaccines.