Transient arterial insufficiency and neurologic deficit following external iliac vein stent reconstruction for malignant compression.

Acute iliofemoral deep vein thrombosis may present with pain and swelling or phlegmasia cerulea dolens. When thrombosis occurs in the setting of an underlying venous obstruction, stent reconstruction should be performed after thrombus clearance to prevent rethrombosis. Stent reconstruction after thrombus clearance is associated with high technical success rates and durable patency. This report describes transient lower extremity arterial insufficiency and neurologic deficit after external iliac vein stent expansion and reconstruction within a confined space resulting from a malignant obstruction. It serves as a cautionary tale that, in rare cases, aggressive venous stenting within a confined space can transfer clinically significant forces to adjacent arteries and nerves.

Publisher Correction: Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington's disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington's disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Publisher Correction: Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington's disease.

The original version of this Article incorrectly gave a publication date of 8 October 2018; this should have been 28 September 2018. This has now been corrected in the PDF and HTML versions of the Article.

Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington's disease.

Huntington's disease is a progressive neurodegenerative disorder caused by polyglutamine-expanded mutant huntingtin (mHTT). Here, we show that the deubiquitinase Usp12 rescues mHTT-mediated neurodegeneration in Huntington's disease rodent and patient-derived human neurons, and in Drosophila. The neuroprotective role of Usp12 may be specific amongst related deubiquitinases, as the closely related homolog Usp46 does not suppress mHTT-mediated toxicity. Mechanistically, we identify Usp12 as a potent inducer of neuronal autophagy. Usp12 overexpression accelerates autophagic flux and induces an approximately sixfold increase in autophagic structures as determined by ultrastructural analyses, while suppression of endogenous Usp12 slows autophagy. Surprisingly, the catalytic activity of Usp12 is not required to protect against neurodegeneration or induce autophagy. These findings identify the deubiquitinase Usp12 as a regulator of neuronal proteostasis and mHTT-mediated neurodegeneration.

Serine 421 regulates mutant huntingtin toxicity and clearance in mice.

Huntington's disease (HD) is a progressive, adult-onset neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the N-terminal region of the protein huntingtin (HTT). There are no cures or disease-modifying therapies for HD. HTT has a highly conserved Akt phosphorylation site at serine 421, and prior work in HD models found that phosphorylation at S421 (S421-P) diminishes the toxicity of mutant HTT (mHTT) fragments in neuronal cultures. However, whether S421-P affects the toxicity of mHTT in vivo remains unknown. In this work, we used murine models to investigate the role of S421-P in HTT-induced neurodegeneration. Specifically, we mutated the human mHTT gene within a BAC to express either an aspartic acid or an alanine at position 421, mimicking tonic phosphorylation (mHTT-S421D mice) or preventing phosphorylation (mHTT-S421A mice), respectively. Mimicking HTT phosphorylation strongly ameliorated mHTT-induced behavioral dysfunction and striatal neurodegeneration, whereas neuronal dysfunction persisted when S421 phosphorylation was blocked. We found that S421 phosphorylation mitigates neurodegeneration by increasing proteasome-dependent turnover of mHTT and reducing the presence of a toxic mHTT conformer. These data indicate that S421 is a potent modifier of mHTT toxicity and offer in vivo validation for S421 as a therapeutic target in HD.

Sequence-Level Analysis of the Major European Huntington Disease Haplotype.

Huntington disease (HD) reflects the dominant consequences of a CAG-repeat expansion in HTT. Analysis of common SNP-based haplotypes has revealed that most European HD subjects have distinguishable HTT haplotypes on their normal and disease chromosomes and that ∼50% of the latter share the same major HD haplotype. We reasoned that sequence-level investigation of this founder haplotype could provide significant insights into the history of HD and valuable information for gene-targeting approaches. Consequently, we performed whole-genome sequencing of HD and control subjects from four independent families in whom the major European HD haplotype segregates with the disease. Analysis of the full-sequence-based HTT haplotype indicated that these four families share a common ancestor sufficiently distant to have permitted the accumulation of family-specific variants. Confirmation of new CAG-expansion mutations on this haplotype suggests that unlike most founders of human disease, the common ancestor of HD-affected families with the major haplotype most likely did not have HD. Further, availability of the full sequence data validated the use of SNP imputation to predict the optimal variants for capturing heterozygosity in personalized allele-specific gene-silencing approaches. As few as ten SNPs are capable of revealing heterozygosity in more than 97% of European HD subjects. Extension of allele-specific silencing strategies to the few remaining homozygous individuals is likely to be achievable through additional known SNPs and discovery of private variants by complete sequencing of HTT. These data suggest that the current development of gene-based targeting for HD could be extended to personalized allele-specific approaches in essentially all HD individuals of European ancestry.

Tau reduction prevents Abeta-induced defects in axonal transport.

Amyloid-ß (Aß) peptides, derived from the amyloid precursor protein, and the microtubule-associated protein tau are key pathogenic factors in Alzheimer's disease (AD). How exactly they impair cognitive functions is unknown. We assessed the effects of Aß and tau on axonal transport of mitochondria and the neurotrophin receptor TrkA, cargoes that are critical for neuronal function and survival and whose distributions are altered in AD. Aß oligomers rapidly inhibited axonal transport of these cargoes in wild-type neurons. Lowering tau levels prevented these defects without affecting baseline axonal transport. Thus, Aß requires tau to impair axonal transport, and tau reduction protects against Aß-induced axonal transport defects.

Evaluation of methods that locate the center of the ankle for computer-assisted total knee arthroplasty.

Accurate alignment of the mechanical axis of the limb is important to the success of a total knee arthroplasty. Although computer-assisted navigation systems can align implants more accurately than traditional mechanical guides, the ideal technique to determine the distal end point of the mechanical axis, the center of the ankle, is unknown. In this study, we evaluated the accuracy, precision, objectivity, and speed of five anatomic methods and two kinematic methods for estimating the ankle center in 11 healthy subjects. Magnetic resonance images were used to characterize the shape of the ankle and establish the true ankle center. The most accurate and precise anatomic method was establishing the midpoint of the most medial and most lateral aspects of the malleoli (4.5 +/- 4.1 mm lateral error; 2.7 +/- 4.5 mm posterior error). A biaxial model of the ankle (2.0 +/- 6.4 mm medial error; 0.3 +/- 7.6 mm anterior error) was the most accurate kinematic method. Establishing the midpoint of the most medial and most lateral aspects of the malleoli was an accurate, precise, objective, and fast method for establishing the center of the ankle.