Citations

We report a unique case and presentation of a 77-year-old man with atrial fibrillation who presented with complex imaging features, including bifrontal cerebral hematomas that progressed to multifocal macro- and microhemorrhages, vasogenic edema, and cortical/meningeal enhancement. Cerebrospinal fluid analysis was only remarkable for a protein elevation of 65 mg/dL. Leptomeningeal vessel biopsy failed to demonstrate evidence of amyloid angiopathy but did show concentric obstructive intimal fibroplasia, suggestive of chronic venous congestion. Conventional cerebral angiography showed a Cognard type IV dural arteriovenous fistulae fed by bilateral ethmoidal arteries draining directly into ectatic cortical veins. A chronic occlusion of the anterior third of the superior sagittal sinus was also noted. The fistula was successfully surgically obliterated via an uncomplicated left frontal craniotomy approach. After rehabilitation therapy, he was discharged home with a modified Rankin Scale score of 3. Because effective treatment exists, this case underscores the importance of identifying this rare etiology of intracerebral hemorrhage and pursuing adequate workup.

Abstract Transtendinous abductor tendon repair is a technique the authors described previously to diagnose and treat undersurface tears of the abductor tendons. In this surgical technique article, the authors describe a technique for knotless repair of undersurface tears of the abductor tendons that does not require a transtendinous split or suture passage through the abductor tendon. Because there is no suture passage through the abductor tendon or knot tying, the potential advantages include expeditious technique, compression of tendon against bony footprint, anatomic repair, and avoidance of knots facing the undersurface of the iliotibial band, which may lead to bursal irritation. Technique Video video See video under supplementary data.

There is considerable interest in harnessing innate immunity to treat Alzheimer’s disease (AD). Here, we explore whether a decoy receptor strategy using the ectodomain of select TLRs has therapeutic potential in AD. AAV-mediated expression of human TLR5 ectodomain (sTLR5) alone or fused to human IgG4 Fc (sTLR5Fc) results in robust attenuation of amyloid β (Aβ) accumulation in a mouse model of Alzheimer-type Aβ pathology. sTLR5Fc binds to oligomeric and fibrillar Aβ with high affinity, forms complexes with Aβ, and blocks Aβ toxicity. Oligomeric and fibrillar Aβ modulates flagellin-mediated activation of human TLR5 but does not, by itself, activate TLR5 signaling. Genetic analysis shows that rare protein coding variants in human TLR5 may be associated with a reduced risk of AD. Further, transcriptome analysis shows altered TLR gene expression in human AD. Collectively, our data suggest that TLR5 decoy receptor–based biologics represent a novel and safe Aβ-selective class of biotherapy in AD.

The cellular age distribution of hierarchically organized tissues can reveal important insights into the dynamics of cell differentiation and self-renewal and associated cancer risks. Here, we examine the effect of progenitor compartments with varying differentiation and self-renewal capacities on the resulting observable distributions of replicative cellular ages. We find that strongly amplifying progenitor compartments, i.e. compartments with high self-renewal capacities, substantially broaden the age distributions which become skewed towards younger cells with a long tail of few old cells. For several of these strongly amplifying compartments, the age distribution becomes virtually independent of the influx from the stem cell compartment. By contrast, if tissues are organized into many downstream compartments with low self-renewal capacity, the shape of the replicative cell distribution in more differentiated compartments is dominated by stem cell dynamics with little added variation. In the limiting case of a strict binary differentiation tree without self-renewal, the shape of the output distribution becomes indistinguishable from that of the input distribution. Our results suggest that a comparison of cellular age distributions between healthy and cancerous tissues may inform about dynamical changes within the hierarchical tissue structure, i.e. an acquired increased self-renewal capacity in certain tumours. Furthermore, we compare our theoretical results to telomere length distributions in granulocyte populations of 10 healthy individuals across different ages, highlighting that our theoretical expectations agree with experimental observations.

Abstract BACKGROUND Emergency department (ED) overuse is a costly and often neglected source of postdischarge resource utilization after spine surgery. Failing to investigate drivers of ED visits represents a missed opportunity to improve the value of care in spine patients. OBJECTIVE To identify the prevalence, drivers, and timing of ED visits following elective spine surgery. METHODS Patients undergoing elective spine surgery for degenerative disease at a major medical center were enrolled in a prospective longitudinal registry. Patient and surgery characteristics, and patient-reported outcomes were recorded at baseline and 3 mo after surgery, along with self-reported 90-d ED visits. A multivariable regression model was used to identify independent factors associated with 90-d ED visits. For a sample of patients presenting to our institution's ED, charts were reviewed to identify the reason and time to ED postdischarge. RESULTS Of 2762 patients, we found a 90-d ED visit rate of 9.4%. One-third of patients presented to our institution's ED and of these, 70% presented due to pain or medical concerns at 9 and 7 d postdischarge, respectively, with 60% presenting outside normal clinic hours. Independent risk factors for 90-d ED visits included younger age, preoperative opioid use, chronic obstructive pulmonary disorder, and more vertebral levels involved. CONCLUSION Nearly 10% of elective spine patients had 90-d ED visits not requiring readmission. Pain and medical concerns accounted for 70% of visits at our center, occurring within 10 d of discharge. This study provides the clinical details and a timeline necessary to guide individualized interventions to prevent unnecessary, costly ED visits after spine surgery.

Abstract AL is a rare plasma cell disorder, resulting from clonal bone marrow plasma cells secreting immunoglobulin light chains (LC), which aggregate abnormally into fibrils, and leads to amyloid deposits in different organs. Previous studies using LC immunopurification and MALDI-TOF/MS (MASS-FIX) on patients with known plasma cell disorders (PCDs), demonstrated that monoclonal LC from AL patients display unusually complex mass to charge spectra (m/z) for their LCs at much higher frequencies than other PCDs such as multiple myeloma. We hypothesized that these were post-translational modification, presumably glycoforms. Here, we report investigations into LC glycosylation using MASS- FIX. Serum from 212 lambda and 72 kappa AL patients were collected following Mayo Clinic IRB guidelines. LC was purified from serum using nanobody enrichment method, followed by MASS-FIX. The LCs spectra acquired on MASS-FIX were visually analyzed and were classified into different patterns. The kappa and lambda LC mass distributions with abnormal complex patterns were interrogated for the presence of glycosylation by exposure to the LC to a deglycoslylating enzyme (PNGase F) and analysis of LC mass distribution using MASS-FIX and by LC-ESI-Orbitrap. Monoclonal LCs demonstrating significantly mass shifted peak outside the normal kappa and lambda mass distribution were observed in 31% of kappa and 6% of lambda patients with AL. In order to determine if this characteristic mass shift was due to glycosylation, 16 kappa and 6 lambda LCs were treated with a PNGase F and LC spectrum were re-examined by MASS-FIX and LC-ESI-Orbitrap. The monoclonal LCs whose masses were significantly shifted beyond normal kappa and lambda mass distributions were found to shift to lower molecular weight after PNGase F treatment, confirming the presence of N-glycosylation. Moreover, an additional 5 kappa and 23 lambda samples had other complex patterns, typically with multiple additional peaks at increments of 162 Da. These samples did not shift with PNGase F suggesting either glycation or O-glycosylation. This work is significant as it confirms that N-glycosylated LCs are over represented in patients with AL in comparison to other PCDs. In patients with AL, the frequency of N-glycosylation of kappa LC clones was 5 times higher than that of lambda LC clones. More work is needed to explore the mechanism for this finding, the role of glycosylation in fibril formation, and the other complex patterns observed. In addition, MASS-FIX method used in this work is currently being validated in the clinical lab such that rapid detection of N-glycosylation in patients with monoclonal gammopathies will be possible routinely, potentially leading to earlier clinical suspicion for AL among patients with monoclonal gammopathies and hence to earlier detection of AL. Citation Format: Sanjay Kumar, Angela Dispenzieri, Surendra Dasari, Paolo Milani, Giampaolo Merlini, MeLea Hetrick, David Barnidge, Benjamin Madden, David Murray. Mass spectrometric approach to identify N-glycosylation of light chain in patients with immunoglobulin light chain amyloidosis (AL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2693.