Mystery case: a 63-year-old man with progressive proximal pain and weakness.

A 63-year-old man with a history of type 2 diabetes presented with hip and shoulder pain in June 2010. He was on atorvastatin 80 mg daily and his creatine kinase (CK) was mildly elevated, so he was switched to simvastatin 20 mg daily. Three months later, he was referred to a rheumatologist.

A functional polymorphism in the epidermal growth factor gene predicts hepatocellular carcinoma risk in Japanese hepatitis C patients.

Background: A single nucleotide polymorphism (SNP) in the epidermal growth factor (EGF) gene (rs4444903) has been associated with increased risk of cancer, including hepatocellular carcinoma (HCC). The aim of this study was to examine the relationship between the EGF SNP genotype and the development and prognosis of HCC, in a Japanese population.

Methods: Restriction fragment-length polymorphism was used to determine the presence of the EGF SNP genotype in 498 patients, including 208 patients with HCC.

Connexin 32 and 43 mutations: do they play a role in chronic rhinosinusitis?

Objective: Dysfunction of the sinonasal epithelium may contribute to the pathogenesis of chronic rhinosinusitis (CRS) including recurrent acute rhinosinusitis (RARS). Mutations in connexin 32 and 43 proteins have been associated with a number of human diseases. The objective of this study is to investigate the role of mutations in connexin 32 or connexin 43 genes in CRS and RARS.

Functions and mechanics of dynein motor proteins.

Fuelled by ATP hydrolysis, dyneins generate force and movement on microtubules in a wealth of biological processes, including ciliary beating, cell division and intracellular transport. The large mass and complexity of dynein motors have made elucidating their mechanisms a sizable task. Yet, through a combination of approaches, including X-ray crystallography, cryo-electron microscopy, single-molecule assays and biochemical experiments, important progress has been made towards understanding how these giant motor proteins work.

The ATP costs and time required to degrade ubiquitinated proteins by the 26 S proteasome.

The degradation of ubiquitinated proteins by 26 S proteasomes requires ATP hydrolysis. To investigate if the six proteasomal ATPases function independently or in a cyclic manner, as proposed recently, we used yeast mutants that prevent ATP binding to Rpt3, Rpt5, or Rpt6. Although proteasomes contain six ATPase subunits, each of these single mutations caused a 66% reduction in basal ATP hydrolysis, and each blocked completely the 2-3-fold stimulation of ATPase activity induced by ubiquitinated substrates.

An overview of laparoscopic techniques in abdominal aortic aneurysm repair.

Background: Since 1993, various laparoscopic techniques have been developed to make laparoscopic treatment of abdominal aortic aneurysms (AAAs) a possible therapeutic alternative. We aim to review all published clinical studies on laparoscopic surgery of AAAs and juxtarenal abdominal aortic aneurysms (JAAAs).

Methods: A thorough search of English-language literature published between January 1966 and December 2012 was performed.

Impact of chronic kidney disease on outcomes after abdominal aortic aneurysm repair.

Objective: Chronic kidney disease (CKD) is associated with increased morbidity and death after open abdominal aortic aneurysm (AAA) repair (OAR). This study highlights the effect of CKD on outcomes after endovascular AAA (EVAR) and OAR in contemporary practice.

Methods: The National Surgical Quality Improvement Program (NSQIP) Participant Use File (2005-2008) was queried by Current Procedural Terminology (American Medical Association, Chicago, Ill) code to identify EVAR or OAR patients, who were grouped by CKD class as having mild (CKD class 1 or 2), moderate (CKD class 3), or severe (CKD class 4 or 5) renal disease.

TorsinA participates in endoplasmic reticulum-associated degradation.

TorsinA is an AAA+ ATPase located within the lumen of the endoplasmic reticulum and nuclear envelope, with a mutant form causing early onset torsion dystonia (DYT1). Here we report a new function for torsinA in endoplasmic reticulum-associated degradation (ERAD). Retro-translocation and proteosomal degradation of a mutant cystic fibrosis transmembrane conductance regulator (CFTRΔF508) was inhibited by downregulation of torsinA or overexpression of mutant torsinA, and facilitated by increased torsinA.

Comparable mortality with open repair of complex and infrarenal aortic aneurysm.

Background: A consequence of endovascular aneurysm repair (EVAR) of anatomically straightforward infrarenal abdominal aortic aneurysm repair cohort (AAA) is that open aneurysm repair is more commonly performed for complex anatomy. Complex aneurysm repair with visceral vessel involvement (CAA) or combined aneurysm repair and visceral vessel reconstruction (VVR) has traditionally been considered to increase morbidity and mortality compared with repair of infrarenal AAA. This study evaluated contemporary outcomes of open abdominal aneurysm surgery, including AAA, CAA, and VVR using the National Surgical Quality Improvement Program (NSQIP) database.

The glutamate switch of bacteriophage T7 DNA helicase: role in coupling nucleotide triphosphate (NTP) and DNA binding to NTP hydrolysis.

The DNA helicase encoded by gene 4 of bacteriophage T7 forms a hexameric ring in the presence of dTTP, allowing it to bind DNA in its central core. The oligomerization also creates nucleotide-binding sites located at the interfaces of the subunits. DNA binding stimulates the hydrolysis of dTTP but the mechanism for this two-step control is not clear.

In vivo optical molecular imaging of matrix metalloproteinase activity in abdominal aortic aneurysms correlates with treatment effects on growth rate.

Objectives: We present a method to quantify the inflammatory processes that drive abdominal aortic aneurysm (AAA) development that may help predict the rate of growth and thus guide medical and surgical management. We use an in vivo optical molecular imaging approach to quantify protease activity within the walls of AAAs in a rodent model.

Methods: AAAs were generated in mice by topical application of calcium chloride, followed by the administration of the MMP inhibitor doxycycline for 3 months.

Secondary intervention after endovascular abdominal aortic aneurysm repair.

Objective: Endovascular Abdominal Aortic Aneurysm Repair (EVAR) has been criticized because of the need for frequent secondary interventions (2ndINT) to maintain effective abdominal aortic aneurysm (AAA) exclusion. The study goal is to detail such interventions and determine their effect on clinical outcomes.

Methods: From January 1997 to December 2007, 832 patients underwent EVAR.

TorsinA binds the KASH domain of nesprins and participates in linkage between nuclear envelope and cytoskeleton.

A specific mutation (DeltaE) in torsinA underlies most cases of the dominantly inherited movement disorder, early-onset torsion dystonia (DYT1). TorsinA, a member of the AAA+ ATPase superfamily, is located within the lumen of the nuclear envelope (NE) and endoplasmic reticulum (ER). We investigated an association between torsinA and nesprin-3, which spans the outer nuclear membrane (ONM) of the NE and links it to vimentin via plectin in fibroblasts.

Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice.

Abdominal aortic aneurysm (AAA), an inflammatory disease, involves leukocyte recruitment, immune responses, inflammatory cytokine production, vascular remodeling, neovascularization, and vascular cell apoptosis, all of which contribute to aortic dilatation. This study demonstrates that mast cells, key participants in human allergic immunity, participate in AAA pathogenesis in mice. Mast cells were found to accumulate in murine AAA lesions.

Persistent type 2 endoleak after endovascular repair of abdominal aortic aneurysm is associated with adverse late outcomes.

Objective: Type 2 endoleak occurs in up to 20% of patients after endovascular aneurysm repair (EVAR), but its long-term significance is debated. We reviewed our experience to evaluate late outcomes associated with type 2 endoleak.

Methods: During the interval January 1994 to December 2005, 873 patients underwent EVAR.

Mutant torsinA interferes with protein processing through the secretory pathway in DYT1 dystonia cells.

TorsinA is an AAA(+) protein located predominantly in the lumen of the endoplasmic reticulum (ER) and nuclear envelope responsible for early onset torsion dystonia (DYT1). Most cases of this dominantly inherited movement disorder are caused by deletion of a glutamic acid in the carboxyl terminal region of torsinA. We used a sensitive reporter, Gaussia luciferase (Gluc) to evaluate the role of torsinA in processing proteins through the ER.

Meiotic spindle: sculpted by severing.

Katanin is a conserved AAA ATPase with the ability to sever microtubules, but its biological function in animal cells has been obscure. A recent study using electron tomography has found that katanin stimulates the production of microtubules in the meiotic spindles of Caenorhabditis elegans oocytes.

Dystonia-causing mutant torsinA inhibits cell adhesion and neurite extension through interference with cytoskeletal dynamics.

Early onset torsion dystonia is a movement disorder inherited as an autosomal dominant syndrome with reduced penetrance. Symptoms appear to result from altered neuronal circuitry within the brain with no evidence of neuronal loss. Most cases are caused by loss of a glutamic acid residue in the AAA+ chaperone protein, torsinA, encoded in the DYT1 gene.

Autosomal dominant inclusion body myopathy, Paget disease of bone, and frontotemporal dementia.

Autosomal dominant proximal limb girdle or inclusion body myopathy, associated with Paget disease of bone and frontotemporal dementia (IBMPFD) is a recently described disorder that maps to chromosome 9p21.1-p12. We refined the critical locus and identified the gene as the Valosin Containing Protein (VCP) gene, a member of the AAA-ATPase superfamily using a candidate gene approach.

Role of p97 AAA-ATPase in the retrotranslocation of the cholera toxin A1 chain, a non-ubiquitinated substrate.

The enzymatic A1 chain of cholera toxin retrotranslocates across the endoplasmic reticulum membrane into the cytosol, where it induces toxicity. Almost all other retrotranslocation substrates are modified by the attachment of polyubiquitin chains and moved into the cytosol by the ubiquitin-interacting p97 ATPase complex. The cholera toxin A1 chain, however, can induce toxicity in the absence of ubiquitination, and the motive force that drives retrotranslocation is not known.

Th2-predominant inflammation and blockade of IFN-gamma signaling induce aneurysms in allografted aortas.

Abdominal aortic aneurysms (AAAs) cause death due to complications related to expansion and rupture. The underlying mechanisms that drive AAA development remain largely unknown. We recently described evidence for a shift toward T helper type 2 (Th2) cell responses in human AAAs compared with stenotic atheromas.

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) is a dominant progressive disorder that maps to chromosome 9p21.1-p12. We investigated 13 families with IBMPFD linked to chromosome 9 using a candidate-gene approach.

The early onset dystonia protein torsinA interacts with kinesin light chain 1.

Early onset dystonia is a movement disorder caused by loss of a glutamic acid residue (Glu(302/303)) in the carboxyl-terminal portion of the AAA+ protein, torsinA. We identified the light chain subunit (KLC1) of kinesin-I as an interacting partner for torsinA, with binding occurring between the tetratricopeptide repeat domain of KLC1 and the carboxyl-terminal region of torsinA. Coimmunoprecipitation analysis demonstrated that wild-type torsinA and kinesin-I form a complex in vivo.

EBNA3C coactivation with EBNA2 requires a SUMO homology domain.

Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA3C) is critical for EBV immortalization of infected B lymphocytes and can coactivate the EBV LMP1 promoter with EBNA2. EBNA3C amino acids 365 to 545 are necessary and sufficient for coactivation and are required for SUMO-1 and SUMO-3 interaction. We found that EBNA3C but not EBNA3CDelta343-545 colocalized with SUMO-1 in nuclear bodies and was modified by SUMO-2, SUMO-3, and SUMO-1.