Citations

Propionic acidemia (PA) is an autosomal recessive inborn error of metabolism caused by deficiency of propionyl-CoA carboxylase (PCC). This enzyme is composed of six PCCA and six PCCB subunits and mediates a critical step in catabolism of odd chain fatty acids and certain amino acids. Current treatment options for PA are limited to stringent dietary restriction of protein consumption and some patients undergo elective liver transplantation. We previously generated a hypomorphic model of PA, designated Pcca −/− (A138T), with 2% of wild-type enzyme activity that mimics many aspects of the human disease. In this study, we used the differing tissue tropisms of adeno-associated virus (AAV) to probe the ability of liver or muscle-directed gene therapy to treat systemic aspects of this disease that affects many cell types. Systemic therapy with muscle-biased AAV1, liver-biased AAV8, and broadly tropic AAVrh10 mediated significant biochemical corrections in circulating propionylcarnitine (C3) and methyl citrate by all vectors. The innate tissue bias of AAV1 and AAV8 gene expression was made more specific by the use of muscle-specific muscle creatine kinase (specifically MCK6) and hepatocyte-specific transthyretin (TTR) promoters, respectively. Under these targeted conditions, both vectors mediated significant long-term correction of circulating metabolites, demonstrating that correction of muscle and likely other tissue types in addition to liver is necessary to fully correct pathology caused by PA. Liver-specific AAV8-TTR-PCCA mediated better correction than AAV1-MCK-PCCA. These data suggest that targeted gene therapy may be a viable alternative to liver transplantation for PA. They also demonstrate the effects of tissue-specific and broad gene therapy on a cell autonomous systemic genetic disease.

Purpose This study addressed whether age is prognostic for overall survival (OS) or progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC). Patients and Methods A total of 20,023 patients from 24 first-line clinical trials in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were analyzed. Primary age effects and interactions with age, sex, performance status (PS), and metastatic site were modeled using Cox proportional hazards stratified by treatment arm within study. Results Of total patients, 3,051 (15%) were age ≤ 50 years. Age was prognostic for both OS (P < .001) and PFS (P < .001), with U-shaped risk (ie, highest risk was evident in youngest and oldest patients). Relative to patients of middle age, the youngest patients experienced 19% (95% CI, 7% to 33%) increased risk of death and 22% (95% CI, 10% to 35%) increased risk of progression. The oldest patients experienced 42% (95% CI, 31% to 54%) increased risk of death and 15% (95% CI, 7% to 24%) increased risk of progression or death. This relationship was more pronounced in the first year of follow-up. Age remained marginally significant for OS (P = .08) when adjusted for PS, sex, and presence of liver, lung, or peritoneal metastases, and age was significant in an adjusted model for PFS (P = .005). The age effect did not differ by site of metastatic disease, year of enrollment, type of therapy received, or biomarker mutational status. Conclusion Younger and older age are associated with poorer OS and PFS among treated patients with mCRC. Younger and older patients may represent higher-risk populations, and additional studies are warranted.

Substantial healthcare resources have been devoted to computer navigation and patient-specific instrumentation systems that improve the reproducibility with which neutral mechanical alignment can be achieved following total knee replacement (TKR). This choice of alignment is based on the long-held tenet that the alignment of the limb post-operatively should be within 3° of a neutral mechanical axis. Several recent studies have demonstrated no significant difference in survivorship when comparing well aligned versus malaligned TKRs. Our aim was to review the anatomical alignment of the knee, the historical and contemporary data on a neutral mechanical axis in TKR, and the feasibility of kinematically-aligned TKRs. Review of the literature suggests that a neutral mechanical axis remains the optimal guide to alignment. Cite this article: Bone Joint J 2014;96-B:857–62.

AbstractBackgroundApolipoprotein E ε4 (APOE ε4) is a risk factor for β‐amyloid deposition in Alzheimer's disease dementia. Its influence on β‐amyloid deposition in speech and language disorders, including primary progressive aphasia (PPA), is unclear.MethodsOne hundred thirty subjects with PPA or progressive speech apraxia underwent APOE genotyping and Pittsburgh compound B (PiB) PET scanning. The relationship between APOE ε4 and PiB status, as well as severity and regional distribution of PiB, was assessed.ResultsForty‐five subjects had an APOE ε4 allele and 60 subjects were PiB‐positive. The odds ratio for a subject with APOE ε4 being PiB‐positive compared with a subject without APOE ε4 being PiB‐positive was 10.2 (95% confidence interval, 4.4–25.5; P < .0001). The APOE ε4 allele did not influence regional PiB distribution or severity.ConclusionAPOE ε4 increases the risk of β‐amyloid deposition in PPA and progressive speech apraxia but does not influence regional β‐amyloid distribution or severity.

Objectives/HypothesisApplication to otolaryngology–head and neck surgery residency is highly competitive, and the interview process strives to select qualified applicants with a high aptitude for the specialty. Commonly employed criteria for applicant selection have failed to show correlation with proficiency during residency training. We evaluate the correlation between the results of a surgical aptitude test administered to otolaryngology resident applicants and their performance during residency.Study DesignRetrospective study at an academic otolaryngology–head and neck surgery residency program.MethodsBetween 2007 and 2013, 224 resident applicants participated in a previously described surgical aptitude test administered at a microvascular surgical station. The composite score and attitudinal scores for 24 consecutive residents who matched at our institution were recorded, and their residency performance was analyzed by faculty survey on a five‐point scale. The composite and attitudinal scores were analyzed for correlation with residency performance score by regression analysis.ResultsTwenty‐four residents were evaluated for overall quality as a clinician by eight faculty members who were blinded to the results of surgical aptitude testing. The results of these surveys showed good inter‐rater reliability. Both the overall aptitude test scores and the subset attitudinal score showed reliability in predicting performance during residency training.ConclusionsThe goal of the residency selection process is to evaluate the candidate's potential for success in residency and beyond. The results of this study suggest that a simple‐to‐administer clinical skills test may have predictive value for success in residency and clinician quality.Level of Evidence4 Laryngoscope, 125:E57–E61, 2015

SAGE-Journals-Accessible-Video-Player 10.1089/vid.2014.0017.M1 sj-vid-1-vid-10.1089_vid.2014.0017

ABSTRACTThe ionic liquid 1‐ethyl‐3‐methyl imidazolium chloride (EMIM Cl) and the amino acid l‐arginine hydrochloride (l‐ArgHCl) have been successfully used to improve the yield of oxidative refolding for various proteins. However, the molecular mechanisms behind the actions of such solvent additives—especially of ionic liquids—are still not well understood. To analyze these mechanisms, we have determined the transfer free energies from water into ionic liquid solutions of proteinogenic amino acids and of diketopiperazine as peptide bond analogue. For EMIM Cl and 1‐ethyl‐3‐methyl imidazolium diethyl phosphate, which had a suppressive effect on protein refolding, as well as for l‐ArgHCl favorable interactions with amino acid side chains, but no favorable interactions with the peptide backbone could be observed. A quantitative analysis of other ionic liquids together with their already published effects on protein refolding showed that only solvent additives within a certain range of hydrophobicity, chaotropicity and kosmotropicity were effective for the refolding of recombinant plasminogen activator. © 2014 Wiley Periodicals, Inc. Biopolymers 101: 1129–1140, 2014.