Assessing the efficacy of Alpha1-Proteinase inhibitor (human) augmentation therapy for Alpha1-Antitrypsin deficiency - Related emphysema: Challenges and opportunities.

Clinical benefit of Alpha1-Proteinase Inhibitor (Human) (A1-PI) products for Alpha1-antitrypsin deficiency (AATD) is uncertain, based on a systematic review of observational studies and randomized controlled trials (RCTs) in AATD of Alpha1-Proteinase Inhibitor (Human) (A1-PI) products. At the recommended dose, A1-PI products raise its serum concentration but do not normalize levels. Observational studies suggest A1-PI might modestly slow progression of airflow limitation in patients with intermediate airflow obstruction, a finding not confirmed by three placebo-controlled RCTs of limited power, which showed non-significant rates of forced expiratory volume in 1 s (FEV1) change favoring placebo. These RCTs found trends favoring A1-PI in loss of high-resolution computerized tomographic (HRCT) lung density. While two meta-analyses of HRCT lung density change in RCTs achieved significance favoring A1-PI arms, clinical benefit remains uncertain. HRCT lung density measurements don't distinguish changes in measured density due to fluid shifts into and out of the lungs and changes in lung inflammation from those due to progressive loss of alveolar mass. A meta-analysis of RCTs found exacerbations significantly increased in A1-PI groups compared to placebo. No RCTs have shown favorable effects of A1-PI on mortality, FEV1, 6-min walking distance, quality of life, change in diffusion capacity of carbon monoxide (DLCO), or exacerbation frequency. A fourth RCT comparing two dose regimens of A1-PI is underway. RCTs have not provided evidence of clinical benefit in terms of how patients feel, function, or survive. Results have implications for the design of future clinical trials of A1-PI and potentially other products targeting AATD-associated emphysema.

Personalization of SUDEP risk: A survey of transient subclinical comorbid changes.

OBJECTIVE: Preclinical data report within subject modifiable ailments emerge weeks prior to SUDEP, including sleep disorders and cardiorespiratory changes; findings which support anecdotal clinical data. Here, we bridge preclinical findings with future clinical/preclinical studies, and survey whether caretakers or family members of victims noticed transient changes prior to SUDEP. The aim of this pilot study is to identify potential modifiable changes that may synergistically increase SUDEP risk for future research. METHODS: A mobile electronic survey was posted on SUDEP community websites. The survey queried whether changes in seizures, sleep, physical well-being, emotional well-being, cognition, breathing, or heart rate were noticed before SUDEP. RESULTS: The most profound finding was that 85% of victims had multiple transient ailments prior to SUDEP. Changes in seizures (28/54), and sleep (30/58) occurred in more than 50% of the victims and represent the most influential changes identified. The second and third most influential changes were a reduction in physical well-being (25/57) and emotional well-being (26/56). Changes were observed within the last two months of life in approximately one third of the cases, and more than four months prior to SUDEP in approximately one third of cases, indicating a potential time frame for proactive preventative strategies. Respondents also noted changes in cognition (16/55), breathing (9/54) or heart rate (8/55). Data indicate these changes may be associated with increased SUDEP risk within subject. Study limitations include the responses were based on memory, there was a potential for data to be over reported, and caretakers were not prompted to observe changes a priori, thus some existing changes may have gone unnoticed. SIGNIFICANCE: Data support the preclinical findings that transient, subclinical (i.e., not severe enough to require medical intervention), modifiable ailments may increase risk of SUDEP. This suggests that just as an epilepsy type can change over a lifetime and epilepsy type-specific treatments can reduce SUDEP risk, further personalization of SUDEP risk will improve our understanding as to whether variables contribute to risk differently across lifespan. Thus, with a dynamic capacity to change, differing factors may contribute to the distribution of risk probability within an individual at any given time. Understanding whether different combinations of transient changes are specific to epilepsy type, age, or sex needs to be determined to move the field forward in hopes of developing a personalized approach to preventative strategies.

Readability of American Society of Metabolic Surgery's Patient Information Publications.

INTRODUCTION: Appropriate education and information are the keystones of patient autonomy. Surgical societies support this goal through online informational publications. Despite these recommendations, many of these sources do not provide the appropriate level of reading for the average patient. Multiple national organizations, including the AMA and NIH, have recommended that such materials be written at or below a 6th-grade level. We therefore aimed to evaluate the readability of patient information publications provided by the American Society of Metabolic and Bariatric Surgery (ASMBS). METHODS: Patient information publications were collected from the ASMBS webpage (https://asmbs.org/patients) and evaluated for readability. Microsoft Office was utilized to calculate Flesch Reading Ease (FRE) and Flesch-Kincaid Grade Level (FKGL) scores. Flesch Reading Ease (FRE) is a 0-100 score, with higher scores equating to easier reading (≥80 = 6th-grade reading level). Flesch-Kincaid Grade Level (FKGL) rates text on a US grade school level. Qualitative and univariate analyses were performed. RESULTS: Eleven patient information publications were evaluated. None of the publications achieved an FRE score of 80 or an FKGL of a 6th-grade reading level. The average FRE score was 35.8 (range 14.9-53.6). The average FKGL score was 13.1 (range 10.1-17.5). The publication with the highest FRE and lowest FKGL (best readability) was that for benefits of weight loss. The brochure with the lowest FRE and highest FKGL (worst readability) was that for Medical Tourism. CONCLUSIONS: Although the ASMBS patient information publications are a trusted source of patient literature, none of the 11 publications met the recommended criteria for patient readability. Further refinement of these will be needed to provide the appropriate reading level for the average patient.

Amniotic Band Syndrome: Head-to-Toe Manifestations and Clinical Management Guidelines.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand and describe the basic principles underlying the intrinsic versus extrinsic proposed mechanisms for the development of amniotic band syndrome (ABS). 2. Discuss risk factors and conditions that are associated with the development of ABS. 3. Understand the various presentations and associated clinical implications of ABS by anatomic location. 4. Describe the basic tenets underlying various repair technique options for ABS of the extremities. 5. Discuss the common manifestations of ABS in the face and trunk. 6. Understand clinical implications of fetoscopic surgery as it relates to ABS treatment as a novel method for limb salvage in utero. SUMMARY: Amniotic band syndrome (ABS) refers to the development of constrictive bands of fibrotic tissue in utero. It can lead to a variety of clinical manifestations after delivery. There is much debate in the plastic surgery community regarding the exact pathophysiologic mechanism for the development of ABS, and the most appropriate management. This CME article aims to provide an overview of ABS manifestations throughout the body, and to expound on the most recent advances in anticipatory and definitive management of the condition.

Cervical Collar Clearance in Obtunded Children Presenting Without a Known Traumatic Mechanism: Is Imaging Necessary?

BACKGROUND: Obtunded pediatric patients are often placed in cervical collars (c-collars) to protect their cervical spine (c-spine) while injury is being ruled out, even without a known traumatic injury. The goal of this study was to determine the necessity of c-collars in this population by determining the rate of c-spine injury among patients with suspected non-traumatic mechanisms of loss of consciousness. METHODS: A single institution, ten-year retrospective chart review was conducted including all obtunded patients admitted to the Pediatric Intensive Care Unit without a known traumatic event. Patients were categorized into five groups based on etiology of obtundation: respiratory, cardiac, medical/metabolic, neurologic, and other. Comparisons were made between those placed in a c-collar and a control group who were not, using Wilcoxon rank sum test for continuous measures, and Chi-square or Fisher's exact test for categorical measures. RESULTS: 464 patients were included, of which 39 (8.41%) were placed in a c-collar. There was a significant difference in whether a patient was placed in a c-collar based on diagnosis category (p < 0.001). Those placed in a-c-collar were more likely to undergo imaging studies than the control group (p < 0.001). The overall incidence of c-spine injury in this patient population in our study was zero. CONCLUSION: Cervical collar placement and radiographic evaluation is not necessary in obtunded pediatric patients who present without a known traumatic mechanism as the overall risk of injury is low. Consideration for collar placement should be given in cases when trauma cannot be definitively ruled out at initial evaluation. LEVELS OF EVIDENCE: III.

Making the Case for Virtual Surgical Planning: Bilateral Sequential Fibula Flaps with Immediate Dental Implants for Maxillectomy.

SUMMARY: Oncologic maxillectomy defects requiring bony reconstruction are among the most challenging head and neck cases because of the complex three-dimensional geometry of the midface. Virtual surgical planning technology is advantageous in these cases because it provides superior positional precision and accuracy compared with traditional techniques and facilitates prosthodontic rehabilitation. Maxillary cancer recurrence after an initial fibula flap reconstruction presents a unique challenge. The authors report the first two cases of sequential fibula flaps after second or recurrent cancer of the maxilla. Virtual surgical planning facilitated resection with adequate tumor margins, optimized anatomic positioning of the fibula construct with three-dimensional printed plates, and enabled immediate functional dental implant placement.

Six-year Burden of Care for Nonsyndromic Unilateral Cleft Lip and Palate Patients: A Comparison Between Cleft Centers and Noncleft Centers.

OBJECTIVE: To determine differences in burden of care between nonsyndromic patients with unilateral cleft lip and palate undergoing treatment at American Cleft Palate-Craniofacial Association (ACPA)-accredited centers and nonaccredited centers in New York State. DESIGN: A retrospective review of the New York Statewide Planning and Research Cooperative System database from January 2001 to December 2014 was performed using ICD-9 and CPT coding. PATIENTS, PARTICIPANTS: This study included patients with unilateral cleft lip and palate who underwent both lip and palate repairs during their first 6 years of life. Exclusion criteria included orofacial cleft syndromes, follow-up under 6 years, and one-stage combined cleft lip and palate repairs. RESULTS: Eighty-eight patients were treated at cleft centers, and 29 patients at nonaccredited centers ( n = 117). Age at primary palatoplasty (13.0 months vs 18.1 months; p = .019), total number of cleft operations (2.3 vs 2.7; p = .012), and total number of primary cleft-specific procedures (2.2 vs 2.5; p = .0049) were significantly lower for patients treated in cleft centers. Age at primary cheiloplasty (4.8 months vs 4.6 months; p = .865), post-cheiloplasty length of stay (1.2 days vs 1.2 days; p = .673), post-palatoplasty length of stay (1.5 days vs 1.9 days; p = .211), average hospital admissions (2.2 vs 2.3; p = 0.161), and total complication rates (34.1% vs 21.1%; p = 0.517) did not differ significantly between cleft centers and noncenters. CONCLUSIONS: This data demonstrates some significant differences in overall 6 year burden of care for nonsyndromic patients with unilateral cleft lip and palate treated at ACPA-accredited cleft centers versus nonaccredited centers.

Managing Complications Following Endoscopic Myotomy as a Treatment for Upper Esophageal Sphincter (UES) Achalasia: A Case Report.

Achalasia is a chronic gastrointestinal disorder characterized by increased esophageal sphincter tone and dysmotility that causes worsening dysphagia. While this condition usually affects the lower esophageal sphincter, we present a rare case of upper esophageal sphincter (UES) achalasia of unknown etiology in a female in her sixth decade of life. This was managed via UES myotomy but was complicated by esophageal perforation and severe post-operative stenosis. Consequently, the patient was referred to gastroenterology and treated over the course of two months with six endoscopic dilatations and glucocorticoid injections. Few cases of idiopathic UES achalasia have been described to date.

The HAPPE plus Event-Related (HAPPE+ER) software: A standardized preprocessing pipeline for event-related potential analyses.

Event-Related Potential (ERP) designs are a common method for interrogating neurocognitive function with electroencephalography (EEG). However, the traditional method of preprocessing ERP data is manual-editing - a subjective, time-consuming processes. A number of automated pipelines have recently been created to address the need for standardization, automation, and quantification of EEG data pre-processing; however, few are optimized for ERP analyses (especially in developmental or clinical populations). We propose and validate the HAPPE plus Event-Related (HAPPE+ER) software, a standardized and automated pre-processing pipeline optimized for ERP analyses across the lifespan. HAPPE+ER processes event-related potential data from raw files through preprocessing and generation of event-related potentials for statistical analyses. HAPPE+ER also includes post-processing reports of both data quality and pipeline quality metrics to facilitate the evaluation and reporting of data processing in a standardized manner. Finally, HAPPE+ER includes post-processing scripts to facilitate validating HAPPE+ER performance and/or comparing to performance of other preprocessing pipelines in users' own data via simulated ERPs. We describe multiple approaches with simulated and real ERP data to optimize pipeline performance and compare to other methods and pipelines. HAPPE+ER software is freely available under the terms of GNU General Public License at https://www.gnu.org/licenses/#GPL.

Dorsal Fixation of Coronal Hamate and Fifth Metacarpal Base Fractures: An Anatomic Evaluation of the Ulnar Nerve.

PURPOSE: Traumatic drill overshoot during dorsal fixation of coronal hamate and fifth metacarpal base fractures risks iatrogenic ulnar nerve injury. This study describes the anatomic relationships between exiting volar drill tips and ulnar nerve branches. METHODS: Dorsal drilling of hamate bones and fifth metacarpal bases was performed on cadavers. Dorsal hamate bodies were subdivided into 4 quadrants: (1) distal-ulnar, (2) distal-radial, (3) proximal-ulnar, and (4) proximal-radial. Screws measuring 5 mm more than the dorsal-to-volar bone depths were placed in each quadrant to represent drill exit trajectories with consistent overshoot. A single screw was similarly placed 5 mm distal to the midline articular surface of the dorsal fifth metacarpal base. Distances between estimated drill tips and ulnar nerve branches were measured. RESULTS: Ten cadaver hands were examined. The fifth metacarpal base screw tips directly abutted the ulnar motor branch in 6 hands, and were within 1 mm in 4 hands (mean, 0.4 ± 0.5 mm). Distances from the tips to the ulnar motor and sensory branches were largest in the distal-radial quadrant (11.8 ± 0.8 mm and 9.2 ± 1.9 mm, respectively) and smallest in the proximal-ulnar quadrant (7.3 ± 1.5 mm and 4.3 ± 1.1 mm, respectively). Distances to the ulnar motor and sensory branches were similar between the proximal-ulnar and distal-ulnar quadrants, and between the proximal-radial and distal-radial quadrants. CONCLUSIONS: Dorsal drilling of coronal hamate fractures appears to be safe, as volar drill tips are well away from ulnar nerve motor and sensory branches. Distances to ulnar nerve branches are largest, and theoretically safest, with dorsal drilling in the distal-radial hamate. Dorsal drilling of fifth metacarpal base fractures appears to carry a high risk for potential ulnar motor nerve injury. CLINICAL RELEVANCE: These findings may help minimize potential risks for iatrogenic ulnar nerve injury with dorsal drilling of hamate and fifth metacarpal base fractures.

Combined Treatment of High-Flow Scalp Arteriovenous Malformations.

INTRODUCTION: Appropriate treatment of scalp arteriovenous malformations (SAVMs) remains largely unclear given the rarity of reported cases. This single-institution case series presents consecutive patients with extracranial SAVMs and long-term follow up.The primary aim of this study was to review treatment decisions, evaluate clinical outcomes, and compare our experience to available literature in order to better understand SAVMs and improve future outcomes. MATERIALS AND METHODS: A retrospective review of consecutive patients with extracranial SAVMs between January 2015 and December 2019 was performed. Treatment factors of interest included embolization method, embolic agents, and decision to proceed with surgical resection. Relevant clinical outcomes included recurrence rates, cure rates, and complications. RESULTS: Seven patients were included in the present series. Satisfactory outcomes were ultimately achieved for all 7 patients using embolization with or without combined surgical resection. Embolizations performed in combination with resection were curative in 4 of 4 cases (100%). Embolizations performed without resection were curative in 0 of 4 cases (0%), satisfactory in 2 of 4 cases (50%), and unsatisfactory in 2 of 4 cases (50%). DISCUSSION: All SAVM patients in this series were treated satisfactorily using embolization with or without operative resection. This study strongly suggests that embolization combined with surgical resection during the same admission yields the best treatment outcomes for SAVMs, specifically demonstrating lower rates of recurrence and embolization-related complications. Decisions on whether or not to proceed with resection should be made by the interventional radiologist, the plastic surgeon, and the patient together.

Standardization in Quantitative Imaging: A Multicenter Comparison of Radiomic Features from Different Software Packages on Digital Reference Objects and Patient Data Sets.

Radiomic features are being increasingly studied for clinical applications. We aimed to assess the agreement among radiomic features when computed by several groups by using different software packages under very tightly controlled conditions, which included standardized feature definitions and common image data sets. Ten sites (9 from the NCI's Quantitative Imaging Network] positron emission tomography-computed tomography working group plus one site from outside that group) participated in this project. Nine common quantitative imaging features were selected for comparison including features that describe morphology, intensity, shape, and texture. The common image data sets were: three 3D digital reference objects (DROs) and 10 patient image scans from the Lung Image Database Consortium data set using a specific lesion in each scan. Each object (DRO or lesion) was accompanied by an already-defined volume of interest, from which the features were calculated. Feature values for each object (DRO or lesion) were reported. The coefficient of variation (CV), expressed as a percentage, was calculated across software packages for each feature on each object. Thirteen sets of results were obtained for the DROs and patient data sets. Five of the 9 features showed excellent agreement with CV < 1%; 1 feature had moderate agreement (CV < 10%), and 3 features had larger variations (CV ≥ 10%) even after attempts at harmonization of feature calculations. This work highlights the value of feature definition standardization as well as the need to further clarify definitions for some features.

Renal Forniceal Rupture in the Setting of Obstructing Ureteral Stones: An Analysis of Stone Characterization and Urologic Intervention Pattern.

Introduction and Objective: Forniceal rupture due to obstructing ureterolithiasis (FROU) is a seldom encountered radiographic finding, but the impact of this diagnosis and influence on stone management has not been well studied in the literature. The purpose of the study is to examine stone characteristics and intervention patterns of patients with radiographic evidence of FROU. Materials and Methods: A retrospective analysis of all patients with radiographic evidence of FROU was compared with patients with obstructing ureteral stones without forniceal ruptures (noFROU). All patients presented to our Emergency Department from January 2015 until December 2018. Data analyzed included patient demographics, clinical presentation, stone characteristics, and management pattern. Primary outcome was need for hospital admission and surgical intervention. Results: Thirty-two patients with FROU (mean age = 45) were compared with 50 patients with noFROU (mean age = 57). Univariate analysis revealed that age, history of diabetes mellitus, history of hypertension, days of symptoms, degree of hydronephrosis, and degree of perinephric stranding were associated with forniceal rupture (p ≤ 0.05). On multivariate analysis, only degree of perinephric stranding remained significant (p ≤ 0.05). Average maximum axial stone diameter in the FROU group was 5.1 mm vs 4.7 mm in the noFROU group (p = 0.66). Overall, 68.8% of stones were located within the distal ureter in the FROU group vs 48.8% in the noFROU group (p = 0.09). There was no difference in hospital admission (FROU 37.5% vs noFROU 44%, p = 0.56) and need for surgical intervention (FROU 50% vs noFROU 48%, p = 0.86). There were no 30-day complications in patients with FROU. Conclusions: Ureteral stone location and size does not seem to impact the presence of FROU. FROU may be an alarming reported finding but its presence does not appear to impact clinical outcomes or affect urological management, including admission or need for urologic intervention.

Low-level blast exposure disrupts gliovascular and neurovascular connections and induces a chronic vascular pathology in rat brain.

Much concern exists over the role of blast-induced traumatic brain injury (TBI) in the chronic cognitive and mental health problems that develop in veterans and active duty military personnel. The brain vasculature is particularly sensitive to blast injury. The aim of this study was to characterize the evolving molecular and histologic alterations in the neurovascular unit induced by three repetitive low-energy blast exposures (3 × 74.5 kPa) in a rat model mimicking human mild TBI or subclinical blast exposure. High-resolution two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry of purified brain vascular fractions from blast-exposed animals 6 weeks post-exposure showed decreased levels of vascular-associated glial fibrillary acidic protein (GFAP) and several neuronal intermediate filament proteins (α-internexin and the low, middle, and high molecular weight neurofilament subunits). Loss of these proteins suggested that blast exposure disrupts gliovascular and neurovascular interactions. Electron microscopy confirmed blast-induced effects on perivascular astrocytes including swelling and degeneration of astrocytic endfeet in the brain cortical vasculature. Because the astrocyte is a major sensor of neuronal activity and regulator of cerebral blood flow, structural disruption of gliovascular integrity within the neurovascular unit should impair cerebral autoregulation. Disrupted neurovascular connections to pial and parenchymal blood vessels might also affect brain circulation. Blast exposures also induced structural and functional alterations in the arterial smooth muscle layer. Interestingly, by 8 months after blast exposure, GFAP and neuronal intermediate filament expression had recovered to control levels in isolated brain vascular fractions. However, despite this recovery, a widespread vascular pathology was still apparent at 10 months after blast exposure histologically and on micro-computed tomography scanning. Thus, low-level blast exposure disrupts gliovascular and neurovascular connections while inducing a chronic vascular pathology.

Characterization of highly multiplexed monolithic PET / gamma camera detector modules.

PET detectors use signal multiplexing to reduce the total number of electronics channels needed to cover a given area. Using measured thin-beam calibration data, we tested a principal component based multiplexing scheme for scintillation detectors. The highly-multiplexed detector signal is no longer amenable to standard calibration methodologies. In this study we report results of a prototype multiplexing circuit, and present a new method for calibrating the detector module with multiplexed data. A [Formula: see text] mm3 LYSO scintillation crystal was affixed to a position-sensitive photomultiplier tube with [Formula: see text] position-outputs and one channel that is the sum of the other 64. The 65-channel signal was multiplexed in a resistive circuit, with 65:5 or 65:7 multiplexing. A 0.9 mm beam of 511 keV photons was scanned across the face of the crystal in a 1.52 mm grid pattern in order to characterize the detector response. New methods are developed to reject scattered events and perform depth-estimation to characterize the detector response of the calibration data. Photon interaction position estimation of the testing data was performed using a Gaussian Maximum Likelihood estimator and the resolution and scatter-rejection capabilities of the detector were analyzed. We found that using a 7-channel multiplexing scheme (65:7 compression ratio) with 1.67 mm depth bins had the best performance with a beam-contour of 1.2 mm FWHM (from the 0.9 mm beam) near the center of the crystal and 1.9 mm FWHM near the edge of the crystal. The positioned events followed the expected Beer-Lambert depth distribution. The proposed calibration and positioning method exhibited a scattered photon rejection rate that was a 55% improvement over the summed signal energy-windowing method.

Lack of chronic neuroinflammation in the absence of focal hemorrhage in a rat model of low-energy blast-induced TBI.

Blast-related traumatic brain injury (TBI) has been a common cause of injury in the recent conflicts in Iraq and Afghanistan. Blast waves can damage blood vessels, neurons, and glial cells within the brain. Acutely, depending on the blast energy, blast wave duration, and number of exposures, blast waves disrupt the blood-brain barrier, triggering microglial activation and neuroinflammation. Recently, there has been much interest in the role that ongoing neuroinflammation may play in the chronic effects of TBI. Here, we investigated whether chronic neuroinflammation is present in a rat model of repetitive low-energy blast exposure. Six weeks after three 74.5-kPa blast exposures, and in the absence of hemorrhage, no significant alteration in the level of microglia activation was found. At 6 weeks after blast exposure, plasma levels of fractalkine, interleukin-1ß, lipopolysaccharide-inducible CXC chemokine, macrophage inflammatory protein 1α, and vascular endothelial growth factor were decreased. However, no differences in cytokine levels were detected between blast-exposed and control rats at 40 weeks. In brain, isolated changes were seen in levels of selected cytokines at 6 weeks following blast exposure, but none of these changes was found in both hemispheres or at 40 weeks after blast exposure. Notably, one animal with a focal hemorrhagic tear showed chronic microglial activation around the lesion 16 weeks post-blast exposure. These findings suggest that focal hemorrhage can trigger chronic focal neuroinflammation following blast-induced TBI, but that in the absence of hemorrhage, chronic neuroinflammation is not a general feature of low-level blast injury.

Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, caused by the degeneration of the dopaminergic neurons in the substantia nigra. Mutations in PARK7 (DJ-1) result in early onset autosomal recessive PD, and oxidative modification of DJ-1 has been reported to regulate the protective activity of DJ-1 in vitro. Glutathionylation is a prevalent redox modification of proteins resulting from the disulfide adduction of the glutathione moiety to a reactive cysteine-SH, and glutathionylation of specific proteins has been implicated in regulation of cell viability. Glutaredoxin 1 (Grx1) is the principal deglutathionylating enzyme within cells, and it has been reported to mediate protection of dopaminergic neurons in Caenorhabditis elegans; however many of the functional downstream targets of Grx1 in vivo remain unknown. Previously, DJ-1 protein content was shown to decrease concomitantly with diminution of Grx1 protein content in cell culture of model neurons (SH-SY5Y and Neuro-2A lines). In the current study we aimed to investigate the regulation of DJ-1 by Grx1 in vivo and characterize its glutathionylation in vitro. Here, with Grx(-/-) mice we provide show that Grx1 regulates protein levels of DJ-1 in vivo. Furthermore, with model neuronal cells (SH-SY5Y) we observed decreased DJ-1 protein content in response to treatment with known glutathionylating agents, and with isolated DJ-1 we identified two distinct sites of glutathionylation. Finally, we found that overexpression of DJ-1 in the dopaminergic neurons partly compensates for the loss of the Grx1 homologue in a C. elegans in vivo model of PD. Therefore, our results reveal a novel redox modification of DJ-1 and suggest a novel regulatory mechanism for DJ-1 content in vivo.

Multiplexing strategies for monolithic crystal PET detector modules.

To reduce the number of output channels and associated cost in PET detectors, strategies to multiplex the signal channels have been investigated by several researchers. This work aims to find an optimal multiplexing strategy for detector modules consisting of a monolithic LYSO scintillator coupled to a 64-channel PMT. We apply simulated multiplexing strategies to measured data from two continuous miniature crystal element (cMiCE) detector modules. The strategies tested include standard methods such as row column summation and its variants, as well as new data-driven methods involving the principal components of measured data and variants of those components. The detector positioning resolution and bias are measured for each multiplexing strategy and the results are compared. The mean FWHM over the entire detector was 1.23 mm for no multiplexing (64 channels). Using 16 principal component channels yielded a mean FWHM resolution of 1.21 mm, while traditional row/column summation (16 channels) yielded 1.28 mm. Using 8 principal component output channels resulted in a resolution of 1.30 mm. Using the principal components of the calibration data to guide the multiplexing scheme appears to be a viable method for reducing the number of output data channels. Further study is needed to determine if the depth-of-interaction resolution can be preserved with this multiplexing scheme.

Selective vulnerability of the cerebral vasculature to blast injury in a rat model of mild traumatic brain injury.

BACKGROUND: Blast-related traumatic brain injury (TBI) is a common cause of injury in the military operations in Iraq and Afghanistan. How the primary blast wave affects the brain is not well understood. The aim of the present study was to examine whether blast exposure affects the cerebral vasculature in a rodent model. We analyzed the brains of rats exposed to single or multiple (three) 74.5 kPa blast exposures, conditions that mimic a mild TBI. Rats were sacrificed 24 hours or between 6 and 10 months after exposure. Blast-induced cerebral vascular pathology was examined by a combination of light microscopy, immunohistochemistry, and electron microscopy. RESULTS: We describe a selective vascular pathology that is present acutely at 24 hours after injury. The vascular pathology is found at the margins of focal shear-related injuries that, as we previously showed, typically follow the patterns of penetrating cortical vessels. However, changes in the microvasculature extend beyond the margins of such lesions. Electron microscopy revealed that microvascular pathology is found in regions of the brain with an otherwise normal neuropil. This initial injury leads to chronic changes in the microvasculature that are still evident many months after the initial blast exposure. CONCLUSIONS: These studies suggest that vascular pathology may be a central mechanism in the induction of chronic blast-related injury.

Sclerostin and Pref-1 have differential effects on bone mineral density and strength parameters in adolescent athletes compared with non-athletes.

UNLABELLED: Excessive exercise can have detrimental effects on bone; however, the mechanisms leading to bone loss are not well understood. Sclerostin and preadipocyte factor (Pref)-1 are two hormones which inhibit bone formation. The present study demonstrates that these hormones may have differential effects in athletes as compared to non-athletes. INTRODUCTION: Exercise activity is common in female adolescents, however, excessive exercise can have detrimental effects on bone mineral density (BMD). Mechanisms underlying this decrease in bone mass are not well understood. We investigated the effects of sclerostin, a potent inhibitor of bone formation via WNT signaling inhibition, and Pref-1, a suppressor of osteoblast differentiation, on BMD, bone turnover markers and bone strength in adolescent athletes. METHODS: We studied 50 adolescents between 15-21 years of age: 17 amenorrheic athletes (AA), 17 eumenorrheic athletes (EA), and 16 nonathletic controls (NA). We measured spine and hip BMD by dual energy x-ray absorptiometry and estimated failure load and stiffness at the distal radius and tibia using micro-finite element analysis. We also measured fasting sclerostin, Pref-1, N-terminal propeptide of type 1 procollagen, and C-terminal collagen cross-links levels. RESULTS: Sclerostin levels were higher in AA and EA compared with NA (AA: 0.42 ± 0.15 ng/mL, EA: 0.44 ± 0.09 ng/mL, NA: 0.33 ± 0.14 ng/mL; p = 0.047). In EA, sclerostin was positively associated with lumbar spine (LS) BMD and its Z-score (R = 0.52, p = 0.03 and R = 0.55, p = 0.02, respectively) whereas in NA, sclerostin was inversely associated with LS BMD (R = -0.61, p = 0.01). Pref-1 levels were similar in all three groups and there were significant inverse associations between Pref-1, BMD, and estimated bone strength in NA. CONCLUSIONS: Sclerostin and Pref-1 may have differential effects on bone in adolescent athletes compared to non-athletes.