Can an auditory illusion trick the brain into turning down tinnitus?

Tinnitus, the phantom perception of sound with no external source, affects an estimated 10–15% of the adult population. Current treatments for this oftentimes distressing condition are of limited effectiveness. The “central gain” model proposes that tinnitus arises from an increase in the responsiveness, or gain, of neurons in central auditory pathways, triggered by damage to the auditory periphery. It has been suggested that tinnitus might be treated by compensating for the peripheral damage, thereby restoring normal levels of input to the central pathways, and hence reducing central gain. Unfortunately, when tinnitus originates with permanent damage to the auditory periphery, it may be impossible to compensate for this damage directly. However, we hypothesize that tinnitus may be treated by tricking the brain into believing that it temporarily receives normal levels of input at frequencies where peripheral damage has occurred. We identify an auditory illusion that seems capable, in principle, of achieving this objective. If effective, this approach would offer a safe, accessible, and non-invasive treatment for tinnitus.     

Poly(carbonate urethane) and poly(ether urethane) biodegradation: in vivo studies

Several strategies have been used to increase the biostability of medical-grade polyurethanes while maintaining biocompatibility and mechanical properties. One approach is to chemically modify or replace the susceptible soft segment. Currently, poly(carbonate urethanes) (PCUs) are being evaluated as a replacement of poly(ether urethanes) (PEUs) in medical devices because of the increased oxidative stability of the polycarbonate soft segment. Preliminary in vivo and in vitro studies have reported improved biostability of PCUs over PEUs. Although several studies have reported evidence of in vitro degradation of these new polyurethanes, there has been no evidence of significant in vivo degradation that validates a degradation mechanism. In this study, the effect of soft segment chemistry on the phase morphology, mechanical properties, and in vivo response of commercial-grade PEU and PCU elastomers was examined. Results from dynamic mechanical testing and infrared spectroscopy suggested that the phase separation was better in PCU as compared with PEU. In addition, the higher modulus and reduced ultimate elongation of PCU was attributed to the reduced flexibility of the polycarbonate soft segment. Following material characterization, the in vivo biostability and biocompatibility of PEU and PCU were studied using a subcutaneous cage implant protocol. The results from the cage implant study and cell culture experiments indicated that monocytes adhere, differentiate, and fuse to form foreign body giant cells on both polyurethanes. It is now generally accepted that the reactive oxygen species released by these adherent macrophages and foreign body giant cells initiate PEU biodegradation. Attenuated total reflectance-Fourier transform infrared analysis of explanted samples provided evidence of chain scission and crosslinking in both polyurethanes. This indicated that the PCU was also susceptible to biodegradation by agents released from adherent cells. These results reinforce the need to evaluate and understand the biodegradation mechanisms of PCUs.     

Favorably skewed X‐inactivation accounts for neurological sparing in female carriers of Menkes disease

Desai V, Donsante A, Swoboda KJ, Martensen M, Thompson J, Kaler SG. Favorably skewed X‐inactivation accounts for neurological sparing in female carriers of Menkes disease. Classical Menkes disease is an X‐linked recessive neurodegenerative disorder caused by mutations in ATP7A, which is located at Xq13.1‐q21. ATP7A encodes a copper‐transporting P‐type ATPase and plays a critical role in development of the central nervous system. With rare exceptions involving sex chromosome aneuploidy or X‐autosome translocations, female carriers of ATP7A mutations are asymptomatic except for subtle hair and skin abnormalities, although the mechanism for this neurological sparing has not been reported. We studied a three‐generation family in which a severe ATP7A mutation, a 5.5‐kb genomic deletion spanning exons 13 and 14, segregated. The deletion junction fragment was amplified from the proband by long‐range polymerase chain reaction and sequenced to characterize the breakpoints. We screened at‐risk females in the family for this junction fragment and analyzed their X‐inactivation patterns using the human androgen‐receptor (HUMARA) gene methylation assay. We detected the junction fragment in the proband, two obligate heterozygotes, and four of six at‐risk females. Skewed inactivation of the X chromosome harboring the deletion was noted in all female carriers of the deletion (n = 6), whereas random X‐inactivation was observed in all non‐carriers (n = 2). Our results formally document one mechanism for neurological sparing in female carriers of ATP7A mutations. Based on review of X‐inactivation patterns in female carriers of other X‐linked recessive diseases, our findings imply that substantial expression of a mutant ATP7A at the expense of the normal allele could be associated with neurologic symptoms in female carriers of Menkes disease and its allelic variants, occipital horn syndrome, and ATP7A‐related distal motor neuropathy.     

Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome

Champion KJ, Bunag C, Estep AL, Jones JR, Bolt CH, Rogers RC, Rauen KA, Everman DB. Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome. BRAF, the protein product of BRAF, is a serine/threonine protein kinase and one of the direct downstream effectors of Ras. Somatic mutations in BRAF occur in numerous human cancers, whereas germline BRAF mutations cause cardio‐facio‐cutaneous (CFC) syndrome. One recurrent somatic mutation, p.V600E, is frequently found in several tumor types, such as melanoma, papillary thyroid carcinoma, colon cancer, and ovarian cancer. However, a germline mutation affecting codon 600 has never been described. Here, we present a patient with CFC syndrome and a de novo germline mutation involving codon 600 of BRAF, thus providing the first evidence that a pathogenic germline mutation involving this critical codon is not only compatible with development but can also cause the CFC phenotype. In vitro functional analysis shows that this mutation, which replaces a valine with a glycine at codon 600 (p.V600G), leads to increased ERK and ELK phosphorylation compared to wild‐type BRAF but is less strongly activating than the cancer‐associated p.V600E mutation.     

To tell or not to tell – what to do about p.C282Y heterozygotes identified by HFE screening

Hereditary hemochromatosis (HH) is a common preventable disorder of iron overload that can result in liver cirrhosis and reduced lifespan. Most HH is due to homozygosity for the HFE p.C282Y substitution. We conducted a study of screening for p.C282Y in high schools where p.C282Y heterozygotes (CY) individuals were informed of their genotype by letter. We studied whether these individuals understood the implications of their genotype, whether this resulted in anxiety or reduced health perception and whether cascade testing was higher in families of CY than wild‐type homozygous (CC) individuals. We found 586 of 5757 (1 in 10) screened individuals were CY. One month after receiving their result, 83% correctly answered that they have one copy of p.C282Y. There was no adverse change in anxiety or health perception from prior to screening to 1 month after receiving results. Significantly more family members of CY individuals than CC individuals were informed about HH and had testing for HH. In conclusion, we found that informing CY individuals of their genotype does not increase anxiety and the implications are generally well understood. This leads to cascade testing in a minority of families. CY individuals should be informed of their genetic status when identified by population screening.     

The Composite Severity Score for Lumbar Spine MRI: a Metric of Cumulative Degenerative Disease Predicts Time Spent on Interpretation and Reporting

Conventional measures of radiologist efficiency, such as the relative value unit, fail to account for variations in the complexity and difficulty of a given study. For lumbar spine MRI (LMRI), an ideal performance metric should account for the global severity of lumbar degenerative disease (LSDD) which may influence reporting time (RT), thereby affecting clinical productivity. This study aims to derive a global LSDD metric and estimate its effect on RT. A 10-year archive of LMRI reports comprising 13,388 exams was reviewed. Objective reporting timestamps were used to calculate RT. A natural language processing (NLP) tool was used to extract radiologist-assigned stenosis severity using a 6-point scale (0?=?“normal” to 5?=?“severe”) at each lumbar level. The composite severity score (CSS) was calculated as the sum of each of 18 stenosis grades. The predictive values of CSS, sex, age, radiologist identity, and referring service on RT were examined with multiple regression models. The NLP tool accurately classified LSDD in 94.8% of cases in a validation set. The CSS increased with patient age and differed between men and women. In a univariable model, CSS was a significant predictor of mean RT (R²?=?0.38, p?<?0.001) and independent predictor of mean RT (p?<?0.001) controlling for patient sex, patient age, service location, and interpreting radiologist. The predictive strength of CSS was stronger for the low CSS range (CSS?=?0–25, R²?=?0.83, p?<?0.001) compared to higher CSS values (CSS?>?25, R²?=?0.15, p?=?0.05). Individual radiologist study volume was negatively correlated with mean RT (Pearson’s R?=????0.35, p?<?0.001). The composite severity score predicts radiologist reporting efficiency in LMRI, providing a quantitative measure of case complexity which may be useful for workflow planning and performance evaluation.