Citations

ABSTRACTIntroduction: A 24‐year‐old man with primary hyperoxaluria type 1 (PH1) presented with a rapidly progressive axonal and demyelinating sensorimotor polyradiculoneuropathy shortly after the onset of end‐stage renal disease. His plasma oxalate level was markedly elevated at 107 µmol/L (normal <1.8 µmol/L). Methods: A sural nerve biopsy was performed. Teased fiber and paraffin and epoxy sections were done and morphometric procedures were performed on this sample and on an archived sample from a 22‐year‐old man as an age‐ and gender‐matched control. Embedded teased fiber electron microscopy was also performed. Results: The biopsy revealed secondary demyelination and axonal degeneration. Under polarized light, multiple bright hexagonal, rectangular, and starburst inclusions, typical of calcium oxalate monohydrate crystals, were seen. Conclusions: The proposed mechanisms of nerve damage include disruption of axonal transport due to crystal deposition, toxic effect of oxalate, or nerve ischemia related to vessel occlusion from oxalate crystal deposition. Muscle Nerve 51: 449–454, 2015

OBJECT Delayed cervical palsy (DCP) is a known complication following cervical spine surgery. While most DCPs eventually improve, they can result in significant temporary disability. Postoperative complications affect hospital length of stay (LOS) as well as overall hospital cost. The authors sought to determine the hospital cost of DCP after cervical spine fusion operations. METHODS A retrospective review of patients undergoing cervical fusion for degenerative disease at the Mayo Clinic from 2008 to 2012 was performed. Patients who developed DCPs not attributable to intraoperative trauma were included. All nonoperative-related costs were compared with similar costs in a control group matched according to age, sex, and surgical approach. All costs and services were reflective of the standard costs for the current year. Raw cost data were presented using ratios due to institutional policy against publishing cost data. RESULTS There were 27 patients (18 men, 9 women) who underwent fusion and developed a DCP over the study period. These patients were compared with 24 controls (15 men, 9 women) undergoing fusion in the same time period. There was no difference between patients and controls in mean age (62.4 ± 3.1 years vs 63.8 ± 2.5 years, respectively; p = 0.74), LOS (4.2 ± 3.3 days vs 3.8 ± 4.5 days, respectively; p = 0.43), or operating room–related costs (1.08 ± 0.09 vs 1.0 ± 0.07, respectively; p = 0.58). There was a significant difference in nonoperative hospital-related costs between patients and controls (1.67 ± 0.15 vs 1.0 ± 0.09, respectively; p = 0.04). There was a significantly higher utilization of postoperative imaging (CT or MRI) in the DCP group (14/27, 52%) when compared with the matched cohort (4/24, 17%; p = 0.018), and a significantly higher utilization of physiatry services (24/27 [89%] vs 15/24 [63%], respectively; p = 0.046). CONCLUSIONS While DCPs did not significantly prolong the length of hospitalization, they did increase hospital-related costs. This method could be further extrapolated to model costs of other complications as well.

Abstract Aims Left ventricular systolic elastance (Ees) and diastolic elastance (Eed) correlate with arterial elastance (Ea), but it is unknown how chronic changes in arterial compliance and resistance, which determine Ea, might differentially affect cardiac properties with ageing. We sought to characterize chronic changes in pulsatile and resistive arterial load and correlate them with longitudinal changes in LV structure and function in a prospective, community-based study. Methods and results Comprehensive echocardiography was performed in 722 subjects participating in a randomly selected community-based study at two examinations separated by 4 years, allowing for assessment of LV Ees, Eed, and end-diastolic volume (EDV), Ea, total arterial compliance, and systemic vascular resistance at both examinations. Chronic changes in resistance and heart rate were the dominant contributors to change in Ea. Changes in arterial compliance had little impact on changes in Ea, but were strongly associated with changes in Ees. The combination of increased resistance and decreased compliance was associated with the largest increase in LV diastolic stiffness, an effect that was mediated by a decrease in LVEDV. In contrast, subjects with both improved arterial compliance and decreased resistance displayed an increase in LVEDV over time, with no increase in LV Eed. Conclusion Increases in pulsatile arterial load with ageing contribute more to LV systolic stiffening, while combined pulsatile and resistive loading changes are associated with positive and negative chamber remodelling and diastolic stiffness. Therapies designed to improve arterial resistance and particularly to enhance aortic compliance may hold promise to prevent or reverse cardiac ageing and its sequelae.

Background Atrial fibrillation ( AF ) is associated with increased risk of hospitalization. Little is known about the impact of AF on utilization of noninpatient health care or about sex or race differences in AF ‐related utilization. We examined rates of inpatient and outpatient utilization by AF status in the Atherosclerosis Risk in Communities study. Methods and Results Participants with incident AF enrolled in fee‐for‐service Medicare for at least 12 continuous months between 1991 and 2009 (n=932) were matched on age, sex, race and field center with up to 3 participants without AF (n=2729). Healthcare utilization was ascertained from Medicare claims and classified by primary International Classification of Diseases, ninth revision code. The average annual numbers of days hospitalized were 13.2 (95% CI 11.6 to 15.0) and 2.8 (95% CI 2.5 to 3.1) for those with and without AF , respectively. The corresponding numbers of annual outpatient claims were 53.3 (95% CI 50.5 to 56.3) and 22.9 (95% CI 22.1 to 23.8) for those with and without AF , respectively. Most utilization among AF patients was attributable to non‐ AF conditions. The adjusted rate ratio for annual days hospitalized for other cardiovascular disease–related reasons was 4.58 (95% CI : 3.41 to 6.16) for those with AF versus those without AF . The association between AF and healthcare utilization was similar among men and women and among white and black participants. Conclusions Participants with AF had considerably greater healthcare utilization, and the difference in utilization for other cardiovascular disease –related reasons was substantial. In addition to rate or rhythm treatment, AF management should focus on the accompanying cardiovascular comorbidities.

ABSTRACT Replication-competent adenoviral (RC-Ad) vectors generate exceptionally strong gene-based vaccine responses by amplifying the antigen transgenes they carry. While they are potent, they also risk causing adenovirus infections. More common replication-defective Ad (RD-Ad) vectors with deletions of E1 avoid this risk but do not replicate their transgene and generate markedly weaker vaccine responses. To amplify vaccine transgenes while avoiding production of infectious progeny viruses, we engineered “single-cycle” adenovirus (SC-Ad) vectors by deleting the gene for IIIa capsid cement protein of lower-seroprevalence adenovirus serotype 6. In mouse, human, hamster, and macaque cells, SC-Ad6 still replicated its genome but prevented genome packaging and virion maturation. When used for mucosal intranasal immunization of Syrian hamsters, both SC-Ad and RC-Ad expressed transgenes at levels hundreds of times higher than that of RD-Ad. Surprisingly, SC-Ad, but not RC-Ad, generated higher levels of transgene-specific antibody than RD-Ad, which notably climbed in serum and vaginal wash samples over 12 weeks after single mucosal immunization. When RD-Ad and SC-Ad were tested by single sublingual immunization in rhesus macaques, SC-Ad generated higher gamma interferon (IFN-γ) responses and higher transgene-specific serum antibody levels. These data suggest that SC-Ad vectors may have utility as mucosal vaccines. IMPORTANCE This work illustrates the utility of our recently developed single-cycle adenovirus (SC-Ad6) vector as a new vaccine platform. Replication-defective (RD-Ad6) vectors produce low levels of transgene protein, which leads to minimal antibody responses in vivo . This study shows that replicating SC-Ad6 produces higher levels of luciferase and induces higher levels of green fluorescent protein (GFP)-specific antibodies than RD in a permissive Syrian hamster model. Surprisingly, although a replication-competent (RC-Ad6) vector produces more luciferase than SC-Ad6, it does not elicit comparable levels of anti-GFP antibodies in permissive hamsters. When tested in the larger rhesus macaque model, SC-Ad6 induces higher transgene-specific antibody and T cell responses. Together, these data suggest that SC-Ad6 could be a more effective platform for developing vaccines against more relevant antigens. This could be especially beneficial for developing vaccines for pathogens for which traditional replication-defective adenovirus vectors have not been effective.

COMMD1 deficiency results in defective copper homeostasis, but the mechanism for this has remained elusive. Here we report that COMMD1 is directly linked to early endosomes through its interaction with a protein complex containing CCDC22, CCDC93, and C16orf62. This COMMD/CCDC22/CCDC93 (CCC) complex interacts with the multisubunit WASH complex, an evolutionarily conserved system, which is required for endosomal deposition of F-actin and cargo trafficking in conjunction with the retromer. Interactions between the WASH complex subunit FAM21, and the carboxyl-terminal ends of CCDC22 and CCDC93 are responsible for CCC complex recruitment to endosomes. We show that depletion of CCC complex components leads to lack of copper-dependent movement of the copper transporter ATP7A from endosomes, resulting in intracellular copper accumulation and modest alterations in copper homeostasis in humans with CCDC22 mutations. This work provides a mechanistic explanation for the role of COMMD1 in copper homeostasis and uncovers additional genes involved in the regulation of copper transporter recycling.

AbstractPyoderma gangrenosum is a chronic sterile skin disorder that is frequently seen in association with systemic disorders such as inflammatory bowel disease. Extracutaneous pyoderma gangrenosum is rare and most commonly occurs in the lungs. It is particularly unusual for extracutaneous pyoderma gangrenosum to manifest prior to skin findings and without an associated systemic disorder. A 19‐year‐old white man presented with shortness of breath and a productive cough. His skin exam was normal. Unenhanced chest computed tomography showed peripheral consolidations, areas of cavitation, nodules and bilateral pleural effusions. A bronchoalveolar lavage and an autoimmune panel were unremarkable. Right lung wedge biopsies via thoracostomy was performed and showed pulmonary pyoderma gangrenosum. He was treated with corticosteroids and has returned back to his baseline. This is the first case of pulmonary pyoderma gangrenosum without any associated underlying systemic disorder and without any cutaneous manifestations to date. Serial follow‐ups are necessary to assess for the development of an associated systemic disorder or skin lesions.