Yeast Models for the Study of Amyloid-Associated Disorders and Development of Future Therapy

First described almost two decades ago, the pioneering yeast models of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases, have become well-established research tools, providing both basic mechanistic insights as well as a platform for the development of therapeutic agents. These maladies are associated with the formation of aggregative amyloid protein structures showing common characteristics, such as the assembly of soluble oligomeric species, binding of indicative dyes, and apoptotic cytotoxicity. The canonical yeast models have recently been expanded by the establishment of a model for type II diabetes, a non-neurological amyloid-associated disease. While these model systems require the exogenous expression of mammalian proteins in yeast, an additional amyloid-associated disease model, comprising solely mutations of endogenous yeast genes, has been recently described. Mutated in the adenine salvage pathway, this yeast model exhibits adenine accumulation, thereby recapitulating adenine inborn error of metabolism disorders. Moreover, in line with the recent extension of the amyloid hypothesis to include metabolite amyloids, in addition to protein-associated ones, the intracellular assembly of adenine amyloid-like structures has been demonstrated using this yeast model. In this review, we describe currently available yeast models of diverse amyloid-associated disorders, as well as their impact on our understanding of disease mechanisms and contribution to future potential drug development

Multidisciplinary surgical approach for cerebrospinal fluid leak in children with complex head trauma

Abstract Introduction Post-traumatic cerebrospinal fluid leak from the anterior cranial fossa in children may be isolated or combined with severe facial and calvarial injury. Untreated leak may result with meningitis, hydrocephalus, and abnormal neurocognitive development. Patients and methods We present nine children, ages 4-16 years, with complicated craniofacial injury treated by a combined subcranial and intracranial approach. A continuous lumbar drainage was kept for several days, and prophylactic antibiotics and anti-convulsive medications were routinely given. A multidisciplinary approach including discussion before surgery about other surgical options (endoscopic extracranial and intracranial alone) were performed. Results None of the operated children had episodes of meningitis/leak after the combined approach, suggesting that appropriate sealing of the base of the skull has been achieved. There was no mortality, and the long-term follow-up showed good developmental and cosmetic results. Most of the children had significant brain contusions prior to surgery; however, these did not progress as minimal retraction was enabled by the extensive subcranial and intracranial approach. Conclusions Child's age, anatomy of the bone, extent of cranial injury, and clinical parameters should be seriously considered when choosing the technical methods as for sealing base of skull and reconstruction of facial/cranial bones. Young age does not seem to be a contraindication to the combined approach, thus, we recommend considering it in extensive base of skull fractures when concomitant cranial, maxillofacial, and orbital fractures coexist, as alternative options may not suffice in these cases

Clinical Results of Atticoantrotomy with Attic Reconstruction or Attic Obliteration for Patients with an Attic Cholesteatoma

ObjectivesWe aimed to investigate the clinical results of atticoantrotomy in patients with an attic cholesteatoma.MethodsNinety-eight ears in 98 patients were operated on using atticoantrotomy between October 2002 and December 2006. A retrospective review of the otology database (operative findings and methods, postoperative physical examination and pre- and postoperative audiometry) was performed.ResultsThere were 58 female and 40 male patients with a mean age of 40 yr. The cholesteatoma was limited to the attic region in 24 patients (24.5%); attic with antrum in 18 (18.4%); and attic with antrum and middle ear in 56 (57.1%). Attic obliteration was performed in 59 patients (60.2%), attic reconstruction in 39 (39.8%) and ossicular reconstruction was performed in 59 (60.2%). The mean preoperative and postoperative air-bone gaps were 29.2±13.5 dB and 25.0±15.4 dB, respectively (P=0.01) and the mean preoperative and postoperative high-tone bone conduction levels were 14.5±9.7 dB and 15.23±14.0 dB, respectively (P=0.411). A recurrent cholesteatoma was detected in 3 ears (3%) and revision surgery was performed on these patients.ConclusionAtticoantrotomy showed a low recurrence rate and no deterioration in hearing levels. If there is a intact malleus head or body of incus, attic reconstruction was possible and this procedure could lead to improved hearing. However, postoperative retraction occurred in 18% of patients, a problem that will need to be solved in the future