Test-retest reliability of FreeSurfer-derived volume, area and cortical thickness from MPRAGE and MP2RAGE brain MRI images.

Background and purpose: Large MRI studies often pool data gathered from widely varying imaging sequences. Pooled data creates a potential source of variation in structural analyses which may cause misinterpretation of findings. The purpose of this study is to determine if data acquired using different scan sequences, head coils and scanners offers consistent structural measurements. Materials and methods: Participants (163 right-handed males: 82 typically developing controls, 81 participants with autism spectrum disorder) were scanned on the same day using an MPRAGE sequence with a 12-channel headcoil on a Siemens 3T Trio scanner and an MP2RAGE sequence with a 64-channel headcoil on a Siemens 3T Prisma scanner. Segmentation was performed using FreeSurfer to identify regions exhibiting variation between sequences on measures of volume, surface area, and cortical thickness. Intraclass correlation coefficient (ICC) and mean percent difference (MPD) were used as test-retest reproducibility measures. Results: ICC for total brain segmented volume yielded a 0.99 intraclass correlation, demonstrating high overall volumetric reproducibility. Comparison of individual regions of interest resulted in greater variation. Volumetric variability, although low overall, was greatest in the entorhinal cortex (ICC = 0.71), frontal (ICC = 0.60) and temporal (ICC = 0.60) poles. Surface area variability was greatest in the insula (ICC = 0.65), temporal (ICC = 0.64) and frontal (ICC = 0.68) poles. Cortical thickness was most variable in the frontal (ICC = 0.41) and temporal (ICC = 0.35) poles. Conclusion: Data collected on different scanners and head coils using MPRAGE and MP2RAGE are generally consistent for surface area and volume estimates. However, regional variability may constrain accuracy in some regions and cortical thickness measurements exhibit higher generalized variability.

The acute effects of passive heating on endothelial function, muscle microvascular oxygen delivery, and expression of serum HSP90α.

Passive heating has been a therapeutic tool used to elevate core temperature and induce increases in cardiac output, blood flow, and shear stress. We aimed to determine the effects of a single bout of passive heating on endothelial function and serum heat shock protein 90α (HSP90α) levels in young, healthy subjects. 8 healthy subjects were recruited to participate in one bout of whole-body passive heating via immersion in a 40 °C hot tub to maintain a 1 °C increase in rectal temperature for 60 min. Twenty-four hours after heating, shear-rate corrected endothelium-dependent dilation increased (pre: 0.004 ± 0.002%SRAUC; post: 0.006 ± 0.003%SRAUC; p = 0.034) but serum [HSP90α] was not changed (pre: 36.7 ± 10.3 ng/mL; post: 40.6 ± 15.9 ng/mL; p = 0.39). Neither resting muscle O2 utilization (pre: 0.17 ± 0.11 mL O2 min-1 (100 g)-1; post: 0.14 ± 0.09 mL O2 min-1 (100 g)-1); p = 0.28) nor mean arterial pressure (pre: 74 ± 11 mmHg; post: 73 ± 11 mmHg; p = 0.79) were influenced by the heating intervention. Finally, time to peak after cuff release was significantly delayed for % O2 sat (TTPpre = 39 ± 8.9 s and TTPpost = 43.5 ± 8.2 s; p = 0.007) and deoxy-[heme] (TTPpre = 41.3 ± 18.1 s and TTPpost = 51.4 ± 16.3 s; p = 0.018), with no effect on oxy-[heme] (p = 0.19) and total-[heme] (p = 0.41). One bout of passive heating improved endothelium-dependent dilation 24 h later in young, healthy subjects. This data suggests that passive heat treatments may provide a simple intervention for improving vascular health.

Sport-Related Concussion Preceding Adrenal Insufficiency and Hypopituitarism.

ABSTRACT: A 49-year-old woman with a history of daily inhaled corticosteroid use for asthma presented to a concussion clinic 7 wk after sport-related head injury with headache, visual blurring, dizziness, nausea, fatigue, polydipsia, and polyuria. Examination revealed difficulty with vestibulo-occulomotor testing due to nausea and visual straining. Cranial CT/MR imaging was unremarkable. Laboratory testing revealed critically low serum cortisol, hypernatremia, and urine studies suggesting diabetes insipidus. The patient was referred to the emergency department. Intravenous fluid resuscitation, corticosteroids, and desmopressin led to significant symptomatic relief. She was maintained on oral hydrocortisone after cosyntropin test revealed adrenal insufficiency. Her clinical picture suggested chronic subclinical adrenal suppression from inhaled corticosteroids, which was exacerbated by hypopituitarism possibly from concussion combined with diabetes insipidus. Adrenal insufficiency should be considered in athletes with history of corticosteroid use and endocrine-related symptoms after concussion, because this can create significant morbidity and can mimic traditional symptoms of concussion.

Pericapsular nerve group (PENG) block provides improved short-term analgesia compared with the femoral nerve block in hip fracture surgery: a single-center double-blinded randomized comparative trial.

BACKGROUND: The femoral nerve block (FNB) may be used for analgesia in hip fracture surgery. The pericapsular nerve group (PENG) block is a novel regional technique and may provide better pain reduction while preserving motor function, but these blocks have not been directly compared. METHODS: In a single-center double-blinded randomized comparative trial, patients presenting for hip fracture surgery received analgesia with either FNB or PENG block. The primary outcome measure was pain scores (Numeric Rating Scale (NRS) 0 to 10). Secondary outcomes were postoperative quadriceps strength, opiate use, complications, length of hospital stay, and patient-reported outcomes. RESULTS: Sixty patients were randomized and equally allocated between groups. Baseline demographics were similar. Postoperatively in recovery (day 0), the PENG group experienced less pain compared with the FNB group. (In the PENG group, 63% experienced no pain, 27% mild pain, and 10% moderate to severe pain. In comparison, 30% of the FNB group reported no pain, 27% mild pain, and 36% moderate to severe pain; p=0.04). This was assessed using an 11-point Likert NRS. Quadriceps strength was better preserved in the PENG group in the recovery unit (assessed using Oxford muscle strength grading, 60% intact in the PENG group vs none intact in the FNB group; p<0.001) and on day 1 (90% intact vs 50%, respectively; p=0.004). There was no difference in other outcomes. CONCLUSIONS: Patients receiving a PENG block for intraoperative and postoperative analgesia during hip fracture surgery experience less postoperative pain in the recovery room with no difference detected by postoperative day 1. Quadriceps strength was better preserved with the PENG block. Despite the short-term analgesic benefit and improved quadriceps strength, there were no differences detected in the quality of recovery.

Limb blood flow and muscle oxygenation responses during handgrip exercise above vs. below critical force.

This study compared the brachial artery blood flow (Q̇BA) and microvascular oxygen delivery responses during handgrip exercise above vs. below critical force (CF; the isometric analog of critical power). Q̇BA and microvascular oxygen delivery are important determinants of oxygen utilization and metabolite accumulation during exercise, both of which increase progressively during exercise above CF. However the Q̇BA and microvascular oxygen delivery responses above vs. below CF remain unknown. We hypothesized that Q̇BA, deoxygenated-heme (deoxy-[heme]; an estimate of microvascular fractional oxygen extraction), and total-heme concentrations (total-[heme]; an estimate of changes in microvascular hematocrit) would demonstrate physiological maximums above CF despite increases in exercise intensity. Seven men and six women performed 1) a 5-min rhythmic isometric-handgrip maximal-effort test (MET) to determine CF and 2) two constant target-force tests above (severe-intensity; S1 and S2) and two constant target-force tests below (heavy-intensity; H1 and H2) CF. CF was 189.3 ± 16.7 N (29.7 ± 1.6%MVC). At end-exercise, Q̇BA was greater for tests above CF (S1: 418 ± 147 mL/min; S2: 403 ± 137 mL/min) compared to tests below CF (H1: 287 ± 97 mL/min; H2: 340 ± 116 mL/min; all p < 0.05) but was not different between S1 and S2. Further, end-test Q̇BA during both tests above CF was not different from Q̇BA estimated at CF (392 ± 37 mL/min). At end-exercise, deoxy-[heme] was not different between tests above CF (S1: 150 ± 50 µM; S2: 155 ± 57 µM), but was greater during tests above CF compared to tests below CF (H1: 101 ± 24 µM; H2: 111 ± 21 µM; all p < 0.05). At end-exercise, total-[heme] was not different between tests above CF (S1: 404 ± 58 µM; S2: 397 ± 73 µM), but was greater during tests above CF compared to H1 (352 ± 58 µM; p < 0.01) but not H2 (371 ± 57 µM). These data suggest limb blood flow limitations exist and maximal levels of muscle microvascular oxygen delivery and extraction occur during exercise above, but not below, CF.

Myosin-XVa Controls Both Staircase Architecture and Diameter Gradation of Stereocilia Rows in the Auditory Hair Cell Bundles.

Mammalian hair cells develop their mechanosensory bundles through consecutive phases of stereocilia elongation, thickening, and retraction of supernumerary stereocilia. Many molecules involved in stereocilia elongation have been identified, including myosin-XVa. Significantly less is known about molecular mechanisms of stereocilia thickening and retraction. Here, we used scanning electron microscopy (SEM) to quantify postnatal changes in number and diameters of the auditory hair cell stereocilia in shaker-2 mice (Myo15sh2) that lack both "long" and "short" isoforms of myosin-XVa, and in mice lacking only the "long" myosin-XVa isoform (Myo15∆N). Previously, we observed large mechanotransduction current in young postnatal inner (IHC) and outer (OHC) hair cells of both these strains. Stereocilia counts showed nearly identical developmental retraction of supernumerary stereocilia in control heterozygous, Myo15sh2/sh2, and Myo15∆N/∆N mice, suggesting that this retraction is largely unaffected by myosin-XVa deficiency. However, myosin-XVa deficiency does affect stereocilia diameters. In control, the first (tallest) and second row stereocilia grow in diameter simultaneously. However, the third row stereocilia in IHCs grow only until postnatal day 1-2 and then become thinner. In OHCs, they also grow slower than taller stereocilia, forming a stereocilia diameter gradation within a hair bundle. The sh2 mutation disrupts this gradation and makes all stereocilia nearly identical in thickness in both IHCs and OHCs, with only subtle residual diameter differences. All Myo15sh2/sh2 stereocilia grow postnatally including the third row, which is not a part of normal development. Serial sections with focused ion beam (FIB)-SEM confirmed that diameter changes of Myo15sh2/sh2 IHC and OHC stereocilia resulted from corresponding changes of their actin cores. In contrast to Myo15sh2/sh2, Myo15∆N/∆N hair cells develop prominent stereocilia diameter gradation. Thus, besides building the staircase, the short isoform of myosin-XVa is essential for controlling the diameter of the third row stereocilia and formation of the stereocilia diameter gradation in a hair bundle.

Sport-Related Concussion Preceding Adrenal Insufficiency and Hypopituitarism.

A 49-year-old female with history of daily inhaled corticosteroid use for asthma presented to a concussion clinic 7 wk after sport-related head injury with headache, visual blurring, dizziness, nausea, fatigue, polydipsia, and polyuria. Examination revealed difficulty with vestibuloocculomotor testing due to nausea and visual straining. Cranial computed tomography/magnetic resonance imaging was unremarkable. Laboratory testing revealed critically low serum cortisol, hypernatremia, and urine studies suggesting diabetes insipidus. The patient was referred to the emergency department. Intravenous fluid resuscitation, corticosteroids, and desmopressin led to significant symptomatic relief. She was maintained on oral hydrocortisone after cosyntropin test revealed adrenal insufficiency. Her clinical picture suggested chronic subclinical adrenal suppression from inhaled corticosteroids which was exacerbated by hypopituitarism from concussion combined with diabetes insipidus. Adrenal insufficiency should be considered in athletes with history of corticosteroid use and endocrine-related symptoms after concussion, because this can create significant morbidity and can mimic traditional symptoms of concussion.

Dorsal Amygdala Neurotrophin-3 Decreases Anxious Temperament in Primates.

BACKGROUND: An early-life anxious temperament (AT) is a risk factor for the development of anxiety, depression, and comorbid substance abuse. We validated a nonhuman primate model of early-life AT and identified the dorsal amygdala as a core component of AT's neural circuit. Here, we combine RNA sequencing, viral-vector gene manipulation, functional brain imaging, and behavioral phenotyping to uncover AT's molecular substrates. METHODS: In response to potential threat, AT and brain metabolism were assessed in 46 young rhesus monkeys. We identified AT-related transcripts using RNA-sequencing data from dorsal amygdala tissue (including central nucleus of the amygdala [Ce] and dorsal regions of the basal nucleus). Based on the results, we overexpressed the neurotrophin-3 gene, NTF3, in the dorsal amygdala using intraoperative magnetic resonance imaging-guided surgery (n = 5 per group). RESULTS: This discovery-based approach identified AT-related alterations in the expression of well-established and novel genes, including an inverse association between NTRK3 expression and AT. NTRK3 is an interesting target because it is a relatively unexplored neurotrophic factor that modulates intracellular neuroplasticity pathways. Overexpression of the transcript for NTRK3's endogenous ligand, NTF3, in the dorsal amygdala resulted in reduced AT and altered function in AT's neural circuit. CONCLUSIONS: Together, these data implicate neurotrophin-3/NTRK3 signaling in the dorsal amygdala in mediating primate anxiety. More generally, this approach provides an important step toward understanding the molecular underpinnings of early-life AT and will be useful in guiding the development of treatments to prevent the development of stress-related psychopathology.

Combination therapy with capecitabine and temozolomide in patients with low and high grade neuroendocrine tumors, with an exploratory analysis of O6-methylguanine DNA methyltransferase as a biomarker for response.

Recent advances in the treatment of neuroendocrine tumors (NET), including the combination regimen of capecitabine and temozolomide (CAPTEM), have mostly focused on grade 1 and 2 pancreatic neuroendocrine tumors (pNET). We undertook a retrospective review of 38 patients with advanced NET treated with CAPTEM, including patients with non-pancreatic tumors as well as grade 2 and 3 tumors. O6-methylguanine DNA methyltransferase (MGMT) expression was assessed as a predictive biomarker. We found that CAPTEM demonstrated activity in patients with all grades and in pNET and non-pNET. Median progression free survival (mPFS) was 13.0 months (95% CI: 5.6-17.0) and median overall survival (mOS) 29.3 months (95% CI 17.7 - 45.3). Among evaluable patients, there were 11 (38%) partial responses, 15 (52%) stable disease, and 3 (10%) progressive disease for a disease control rate of 90%. A higher rate of partial responses occurred in patients whose tumors had low levels of MGMT expression (63%) compared to intermediate-high (17%) (p=0.19). Our results show that CAPTEM therapy is active in patients with NET including in previously treated patients and in those with poorly-differentiated histology. We observed a trend towards increased response rate, median PFS, and median OS in patients whose tumors had low MGMT protein expression.

Real-Time Intraoperative MRI Intracerebral Delivery of Induced Pluripotent Stem Cell-Derived Neurons.

Induced pluripotent stem cell (iPSC)-derived neurons represent an opportunity for cell replacement strategies for neurodegenerative disorders such as Parkinson's disease (PD). Improvement in cell graft targeting, distribution, and density can be key for disease modification. We have previously developed a trajectory guide system for real-time intraoperative magnetic resonance imaging (RT-IMRI) delivery of infusates, such as viral vector suspensions for gene therapy strategies. Intracerebral delivery of iPSC-derived neurons presents different challenges than viral vectors, including limited cell survival if cells are kept at room temperature for prolonged periods of time, precipitation and aggregation of cells in the cannula, and obstruction during injection, which must be solved for successful application of this delivery approach. To develop procedures suitable for RT-IMRI cell delivery, we first performed in vitro studies to tailor the delivery hardware (e.g., cannula) and defined a range of parameters to be applied (e.g., maximal time span allowable between cell loading in the system and intracerebral injection) to ensure cell survival. Then we performed an in vivo study to evaluate the feasibility of applying the system to nonhuman primates. Our results demonstrate that the RT-IMRI delivery system provides valuable guidance, monitoring, and visualization during intracerebral cell delivery that are compatible with cell survival.

Overexpressing Corticotropin-Releasing Factor in the Primate Amygdala Increases Anxious Temperament and Alters Its Neural Circuit.

BACKGROUND: Nonhuman primate models are critical for understanding mechanisms underlying human psychopathology. We established a nonhuman primate model of anxious temperament (AT) for studying the early-life risk to develop anxiety and depression. Studies have identified the central nucleus of the amygdala (Ce) as an essential component of AT's neural substrates. Corticotropin-releasing factor (CRF) is expressed in the Ce, has a role in stress, and is linked to psychopathology. Here, in young rhesus monkeys, we combined viral vector technology with assessments of anxiety and multimodal neuroimaging to understand the consequences of chronically increased CRF in the Ce region. METHODS: Using real-time intraoperative magnetic resonance imaging-guided convection-enhanced delivery, five monkeys received bilateral dorsal amygdala Ce-region infusions of adeno-associated virus serotype 2 containing the CRF construct. Their cagemates served as unoperated control subjects. AT, regional brain metabolism, resting functional magnetic resonance imaging, and diffusion tensor imaging were assessed before and 2 months after viral infusions. RESULTS: Dorsal amygdala CRF overexpression significantly increased AT and metabolism within the dorsal amygdala. Additionally, we observed changes in metabolism in other AT-related regions, as well as in measures of functional and structural connectivity. CONCLUSIONS: This study provides a translational roadmap that is important for understanding human psychopathology by combining molecular manipulations used in rodents with behavioral phenotyping and multimodal neuroimaging measures used in humans. The results indicate that chronic CRF overexpression in primates not only increases AT but also affects metabolism and connectivity within components of AT's neural circuitry.

Rebound Body Mass Index Growth in Year-Round Elementary Education Students of Largely Hispanic Descent Undergoing Obesity Interventions.

BACKGROUND: Body mass index (BMI) increases when students are away on summer vacation. Evaluation of serial BMI measurements on year-round students allows new insight into the reasons children gain weight seasonally. METHODS: The 206 first and second graders of 2-year-round elementary schools with obesity intervention programs were weighed and measured every 6 months from April 2011 until April 2013. BMI and BMI percentiles were recorded. RESULTS: Children <50th, 50th to 85th, and 85th to 95th BMI percentiles showed significant accelerated winter gains in BMI (p = 2.6 × 10(-7), p = 6.8 × 10(-10), and p = .0007, respectively) compared with the previous summers. Accelerated BMI growth of the second summer was absent when compared with the previous winter BMI changes in children <95th percentile (p = .48, p = .81, and p = .93). For children >95th percentile, BMI gain continued without significant changes year-round. CONCLUSIONS: School-wide interventions to induce BMI growth limitations are associated with significant rebound BMI gain with possible wintertime augmentation in nonobese children of year-round education programs. Obese children do not display rebound BMI gain, BMI seasonal change, or BMI limitations in response to school-based interventions. School weight control programs should consider off-campus sources of weight gain and be vigilant for rebound and delayed seasonal BMI gains.

Spectrum of Extramammary Malignant Neoplasms in the Breast With Radiologic-Pathologic Correlation.

Although primary breast cancer is the most common malignancy identified by breast imaging, extramammary malignancies may also rarely be encountered. These uncommon lesions may reflect primary neoplasms of nonmammary origin as well as secondary metastatic lesions, and include lymphoma, melanoma, neuroendocrine tumors, gastrointestinal tract malignancies, and angiosarcoma among other entities. Malignant extramammary breast lesions may be encountered during routine mammographic screening, identified during the diagnostic evaluation of a palpable breast abnormality, or may be detected incidentally during imaging of other organs of interest. As such, the radiologist should have familiarity with the appearance of these lesions. This article focuses on a review of several of the most common extramammary metastases to the breast, as well as a few lesions that may develop as either primary or secondary lesions.

Horsetails Are Ancient Polyploids: Evidence from Equisetum giganteum.

Horsetails represent an enigmatic clade within the land plants. Despite consisting only of one genus (Equisetum) that contains 15 species, they are thought to represent the oldest extant genus within the vascular plants dating back possibly as far as the Triassic. Horsetails have retained several ancient features and are also characterized by a particularly high chromosome count (n = 108). Whole-genome duplications (WGDs) have been uncovered in many angiosperm clades and have been associated with the success of angiosperms, both in terms of species richness and biomass dominance, but remain understudied in nonangiosperm clades. Here, we report unambiguous evidence of an ancient WGD in the fern lineage, based on sequencing and de novo assembly of an expressed gene catalog (transcriptome) from the giant horsetail (Equisetum giganteum). We demonstrate that horsetails underwent an independent paleopolyploidy during the Late Cretaceous prior to the diversification of the genus but did not experience any recent polyploidizations that could account for their high chromosome number. We also discuss the specific retention of genes following the WGD and how this may be linked to their long-term survival.

The current health of the signing Deaf community in the UK compared with the general population: a cross-sectional study.

OBJECTIVES: To assess the current health of the Deaf community in the UK and compare with the general population. DESIGN: A quota sample of adult Deaf British Sign Language (BSL) users underwent a health assessment and interview in 2012-2013. Comparative data were obtained from the Health Survey for England (HSE) 2011 and the Quality Outcomes Framework (QOF) 2012. SETTING: Participants completed a structured interview and health assessment at seven Bupa centres across the UK, supported in BSL by Deaf advisers and interpreters. PARTICIPANTS: 298 Deaf people, 20-82 years old, 47% male, with 12% from ethnic minorities. MAIN OUTCOME MEASURES: Self-reported health conditions, medication usage, tobacco and alcohol consumption; measured blood pressure (BP), body mass index, fasting blood sugar and lipid profile. RESULTS: Rates of obesity in the Deaf sample were high, especially in those over 65 years, and 48% were in a high risk group for serious illness. High BP readings were obtained in 37% of Deaf people (21% in HSE): 29% were unaware of this (6% in HSE). Only 42% of Deaf people being treated for hypertension had adequate control, compared with 62% of the general population. Deaf people with self-reported cardiovascular disease (CVD) were significantly less than the general population. One-third of Deaf participants had total cholesterol >5 mmol/L but although control rates were high compared with HSE, treatment rates for self-reported CVD were half the general population rate. Eleven per cent of Deaf participants had blood sugar at prediabetic or diabetic levels, and 77% of those at prediabetic levels were unaware of it. Deaf respondents self-reported more depression (31% of women, 14% of men), but less smoking (8%) and alcohol intake (2-8 units/week). CONCLUSIONS: Deaf people's health is poorer than that of the general population, with probable underdiagnosis and undertreatment of chronic conditions putting them at risk of preventable ill health.

Monte Carlo investigation of collapsed versus rotated IMRT plan verification.

IMRT QA requires, among other tests, a time-consuming process of measuring the absorbed dose, at least to a point, in a high-dose, low-dose-gradient region. Some clinics use a technique of measuring this dose with all beams delivered at a single gantry angle (collapsed delivery), as opposed to the beams delivered at the planned gantry angle (rotated delivery). We examined, established, and optimized Monte Carlo simulations of the dosimetry for IMRT verification of treatment plans for these two different delivery modes (collapsed versus rotated). The results of the simulations were compared to the treatment planning system dose calculations for the two delivery modes, as well as to measurements taken. This was done in order to investigate the validity of the use of a collapsed delivery technique for IMRT QA. The BEAMnrc, DOSXYZnrc, and egs_chamber codes were utilized for the Monte Carlo simulations along with the MMCTP system. A number of different plan complexity metrics were also used in the analysis of the dose distributions in a bid to qualify why verification in a collapsed delivery may or may not be optimal for IMRT QA. Following the Alfonso et al. formalism, the kfclin,frefQclin,Q correction factor was calculated to correct the deviation of small fields from the reference conditions used for beam calibration. We report on the results obtained for a cohort of 20 patients. The plan complexity was investigated for each plan using the complexity metrics of homogeneity index, conformity index, modulation complexity score, and the fraction of beams from a particular plan that intersect the chamber when performing the QA. Rotated QA gives more consistent results than the collapsed QA technique. The kfclin,frefQclin,Qfactor deviates less from 1 for rotated QA than for collapsed QA. If the homogeneity index is less than 0.05 then the kfclin,frefQclin,Q factor does not deviate from unity by more than 1%. A value this low for the homogeneity index can only be obtained with the rotated QA technique.

Titer and product affect the distribution of gene expression after intraputaminal convection-enhanced delivery.

BACKGROUND: The efficacy and safety of intracerebral gene therapy for brain disorders like Parkinson's disease depends on the appropriate distribution of gene expression. OBJECTIVES: To assess whether the distribution of gene expression is affected by vector titer and protein type. METHODS: Four adult macaque monkeys seronegative for adeno-associated virus 5 (AAV5) received a 30-µl inoculation of a high- or a low-titer suspension of AAV5 encoding glial cell line-derived neurotrophic factor (GDNF) or green fluorescent protein (GFP) in the right and left ventral postcommissural putamen. The inoculations were conducted using convection-enhanced delivery and intraoperative MRI (IMRI). RESULTS: IMRI confirmed targeting and infusion cloud irradiation from the catheter tip into the surrounding area. A postmortem analysis 6 weeks after surgery revealed GFP and GDNF expression ipsilateral to the injection site that had a titer-dependent distribution. GFP and GDNF expression was also observed in fibers in the substantia nigra (SN) pars reticulata (pr), demonstrating anterograde transport. Few GFP-positive neurons were present in the SN pars compacta (pc), possibly by direct retrograde transport of the vector. GDNF was present in many neurons of the SNpc and SNpr. CONCLUSIONS: After controlling for target and infusate volume, the intracerebral distribution of the gene product was affected by the vector titer and product biology.

Benchmarking outcomes in the critically injured burn patient.

OBJECTIVE: To determine and compare outcomes with accepted benchmarks in burn care at 6 academic burn centers. BACKGROUND: Since the 1960s, US morbidity and mortality rates have declined tremendously for burn patients, likely related to improvements in surgical and critical care treatment. We describe the baseline patient characteristics and well-defined outcomes for major burn injuries. METHODS: We followed 300 adults and 241 children from 2003 to 2009 through hospitalization, using standard operating procedures developed at study onset. We created an extensive database on patient and injury characteristics, anatomic and physiological derangement, clinical treatment, and outcomes. These data were compared with existing benchmarks in burn care. RESULTS: Study patients were critically injured, as demonstrated by mean % total body surface area (TBSA) (41.2 ± 18.3 for adults and 57.8 ± 18.2 for children) and presence of inhalation injury in 38% of the adults and 54.8% of the children. Mortality in adults was 14.1% for those younger than 55 years and 38.5% for those aged 55 years and older. Mortality in patients younger than 17 years was 7.9%. Overall, the multiple organ failure rate was 27%. When controlling for age and % TBSA, presence of inhalation injury continues to be significant. CONCLUSIONS: This study provides the current benchmark for major burn patients. Mortality rates, notwithstanding significant % TBSA and presence of inhalation injury, have significantly declined compared with previous benchmarks. Modern day surgical and medically intensive management has markedly improved to the point where we can expect patients younger than 55 years with severe burn injuries and inhalation injury to survive these devastating conditions.

Differential effects of two MRI contrast agents on the integrity and distribution of rAAV2 and rAAV5 in the rat striatum.

Intraoperative magnetic resonance imaging (MRI) has been proposed as a method to optimize intracerebral targeting and for tracking infusate distribution in gene therapy trials for nervous system disorders. We thus investigated possible effects of two MRI contrast agents, gadoteridol (Gd) and galbumin (Gab), on the distribution and levels of transgene expression in the rat striatum and their effect on integrity and stability of recombinant adeno-associated virus (rAAV) particles. MRI studies showed that contrast agent distribution did not predict rAAV distribution. However, green fluorescent protein (GFP) immunoreactivity revealed an increase in distribution of rAAV5-GFP, but not rAAV2-GFP, in the presence of Gd when compared with viral vector injected alone. In contrast, Gab increased the distribution of rAAV2-GFP not rAAV5-GFP. These observations pointed to a direct effect of infused contrast agent on the rAAV particles. Negative-stain electron microscopy (EM), DNAase treatment, and differential scanning calorimetry (DSC) were used to monitor rAAV2 and rAAV5 particle integrity and stability following contrast agent incubation. EMs of rAAV2-GFP and rAAV5-GFP particles pretreated with Gd appear morphologically similar to the untreated sample; however, Gab treatment resulted in surface morphology changes and aggregation. A compromise of particle integrity was suggested by sensitivity of the packaged genome to DNAase treatment following Gab incubation but not Gd for both vectors. However, neither agent significantly affected particle stability when analyzed by DSC. An increase in T m was observed for AAV2 in lactated Ringer's buffer. These results thus highlight potential interactions between MRI contrast agents and AAV that might affect vector distribution and stability, as well as the stabilizing effect of lactated Ringer's solution on AAV2.

An investigation into the use of MMCTP to tune accelerator source parameters and testing its clinical application.

This paper presents an alternative method to tune Monte Carlo electron beam parameters to match measured data using a minimal set of variables in order to reduce the model setup time prior to clinical implementation of the model. Monte Carlo calculations provide the possibility of a powerful treatment planning verification technique. The nonstandardized and nonautomated process of tuning the required accelerator model is one of the reasons for delays in the clinical implementation of Monte Carlo techniques. This work aims to establish and verify an alternative tuning method that can be carried out in a minimal amount of time, allowing it to be easily implemented in a clinical setting by personnel with minimal experience with Monte Carlo methods. This tuned model can then be incorporated into the MMCTP system to allow the system to be used as a second dose calculation check for IMRT plans. The technique proposed was used to establish the primary electron beam parameters for accelerator models for the Varian Clinac 2100 6 MV photon beam using the BEAMnrc Monte Carlo system. The method is intended to provide a clear, direct, and efficient process for tuning an accelerator model using readily available clinical quality assurance data. The tuning provides a refined model, which agrees with measured dose profile curves within 1.5% outside the penumbra or 3 mm in the penumbra, for square fields with sides of 3 cm up to 30 cm. These models can then be employed as the basis for Monte Carlo recalculations of dose distributions, using the MMCTP system, for clinical treatment plans, providing an invaluable assessment tool. This was tested on six IMRT plans and compared to the measurements performed for the pretreatment QA process. These Monte Carlo values for the average dose to the chamber volume agreed with measurements to within 0.6%.