Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and ...axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome
c
oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons
,
and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation
.
Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.
To determine whether the CT angiography (CTA) spot sign marks bleeding complications during and after surgery for spontaneous intracerebral hemorrhage (ICH).
In a 2-center study of consecutive ...spontaneous ICH patients who underwent CTA followed by surgical hematoma evacuation, 2 experienced readers (blinded to clinical and surgical data) reviewed CTAs for spot sign presence. Blinded raters assessed active intraoperative and postoperative bleeding. The association between spot sign and active intraoperative bleeding, postoperative rebleeding, and residual ICH volumes was evaluated using univariable and multivariable logistic regression.
A total of 95 patients met inclusion criteria: 44 lobar, 17 deep, 33 cerebellar, and 1 brainstem ICH; ≥1 spot sign was identified in 32 patients (34%). The spot sign was the only independent marker of active bleeding during surgery (odds ratio OR 3.4; 95% confidence interval CI 1.3-9.0). Spot sign (OR 4.1; 95% CI 1.1-17), female sex (OR 6.9; 95% CI 1.7-37), and antiplatelet use (OR 4.6; 95% CI 1.2-21) were predictive of postoperative rebleeding. Larger residual hematomas and postoperative rebleeding were associated with higher discharge case fatality (OR 3.4; 95% CI 1.1-11) and a trend toward increased case fatality at 3 months (OR 2.9; 95% CI 0.9-8.8).
The CTA spot sign is associated with more intraoperative bleeding, more postoperative rebleeding, and larger residual ICH volumes in patients undergoing hematoma evacuation for spontaneous ICH. The spot sign may therefore be useful to select patients for future surgical trials.
We present revised stellar properties for 172 K2 target stars that were identified as possible hosts of transiting planets during Campaigns 1-17. Using medium-resolution near-infrared spectra ...acquired with the NASA Infrared Telescope Facility/SpeX and Palomar/TripleSpec, we found that 86 of our targets were bona fide cool dwarfs, 74 were hotter dwarfs, and 12 were giants. Combining our spectroscopic metallicities with Gaia parallaxes and archival photometry, we derived photometric stellar parameters and compared them to our spectroscopic estimates. Although our spectroscopic and photometric radius and temperature estimates are consistent, our photometric mass estimates are systematically ΔM = 0.11 M (34%) higher than our spectroscopic mass estimates for the least massive stars (M ,phot < 0.4 M ). Adopting the photometric parameters and comparing our results to parameters reported in the Ecliptic Plane Input Catalog, our revised stellar radii are ΔR = 0.15 R (40%) larger, and our revised stellar effective temperatures are roughly ΔTeff = 65 K cooler. Correctly determining the properties of K2 target stars is essential for characterizing any associated planet candidates, estimating the planet search sensitivity, and calculating planet occurrence rates. Even though Gaia parallaxes have increased the power of photometric surveys, spectroscopic characterization remains essential for determining stellar metallicities and investigating correlations between stellar metallicity and planetary properties.
Abstract Background Context Patient-reported outcomes are becoming increasingly important when investigating results of patient and disease management. In sacral tumor, the symptoms of patients can ...vary substantially; therefore, no single questionnaire can adequately account for the full spectrum of symptoms and disability. Purpose The purpose of this study is to analyze redundancy within the current sacral tumor survey and make a recommendation for an updated version based on the results and patient and expert opinions. Study Design/Setting A survey study from a tertiary care orthopedic oncology referral center was used. Patient Sample The patient sample included 70 patients with sacral tumors (78% chordoma). Outcome Measures The following 10 questionnaires included in the current sacral tumor survey were evaluated: the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Item short form, PROMIS Pain Intensity short form, PROMIS Pain Interference short form, PROMIS Neuro-QOL v1.0 Lower Extremity Function short form, PROMIS v1.0 Anxiety short form, the PROMIS v1.0 Depression short form, the International Continence Society Male short form, the Modified Obstruction-Defecation Syndrome questionnaire, the PROMIS Sexual Function Profile v1.0, and the Stoma Quality of Life tool. Methods We performed an exploratory factor analysis to calculate the possible underlying latent traits. Spearman rank correlation coefficients were used to measure to what extent the questionnaires converged. We hypothesized the existence of six domains based on current literature: mental health, physical health, pain, gastrointestinal symptoms, sexual function, and urinary incontinence. To assess content validity, we surveyed 32 patients, 9 orthopedic oncologists, 1 medical oncologist, 1 radiation oncologist, and 1 orthopedic oncology nurse practitioner with experience in treating sacral tumor patients on the relevance of the domains. Results Reliability as measured by Cronbach alpha ranged from 0.65 to 0.96. Coverage measured by floor and ceiling effects ranged from 0% to 52% and from 0% to 30%, respectively. Explanatory factor analysis identified three traits to which the questionnaires that were expected to measure a similar construct correlated the most: mental health, physical function, and pain. Content validity index demonstrated low disagreement among patients (range: 0.10–0.18) and high agreement among physicians (range: 0.91–1.0) on the relevance of the proposed domains. Social health was identified by 50% of the commenting patients as an important yet missing domain. Conclusions The current sacral tumor survey is incomplete and time-consuming, and not all surveys are appropriate for the sacral tumor population. Our recommended survey contains less than half the questions and includes the newly recognized social health domain.
Limited axonal plasticity within the central nervous system (CNS) is a major restriction for functional recovery after CNS injury. The small GTPase RhoA is a key molecule of the converging downstream ...cascade that leads to the inhibition of axonal re-growth. The Rho-pathway integrates growth inhibitory signals derived from extracellular cues, such as chondroitin sulfate proteoglycans, Nogo-A, myelin-associated glycoprotein, oligodendrocyte-myelin glycoprotein, Ephrins and repulsive guidance molecule-A, into the damaged axon. Consequently, the activation of RhoA results in growth cone collapse and finally outgrowth failure. In turn, the inhibition of RhoA-activation blinds the injured axon to its growth inhibitory environment resulting in enhanced axonal sprouting and plasticity. This has been demonstrated in various CNS-injury models for direct RhoA-inhibition and for downstream/upstream blockade of the RhoA-associated pathway. In addition, RhoA-inhibition reduces apoptotic cell death and secondary damage and improves locomotor recovery in clinically relevant models after experimental spinal cord injury (SCI). Unexpectedly, a subset of “small molecules” from the group of non-steroid anti-inflammatory drugs, particularly the FDA-approved ibuprofen, has recently been identified as (1) inhibiting RhoA-activation, (2) enhancing axonal sprouting/regeneration, (3) protecting “tissue at risk” (neuroprotection) and (4) improving motor recovery confined to realistic therapeutical time-frames in clinically relevant SCI models. Here, we survey the effect of small-molecule-induced RhoA-inhibition on axonal plasticity and neurofunctional outcome in CNS injury paradigms. Furthermore, we discuss the body of preclinical evidence for a possible clinical translation with a focus on ibuprofen and illustrate putative risks and benefits for the treatment of acute SCI.
Previous studies suggest that the majority of renal allografts are affected by progressive, severe chronic histologic injury, yet studies using current protocols are lacking. The goal of this study ...was to examine the prevalence and progression of histologic changes using protocol allograft biopsies at 1 and 5 years after solitary kidney transplantation in patients transplanted between 1998 and 2004. Chronic histologic changes generally were mild at both 1 and 5 years and were similar in deceased and living donor kidneys. The overall prevalence of moderate or severe fibrosis was 13% (60/447) at 1 year and 17% (60/343) at 5 years. In a subgroup of 296 patients who underwent both 1‐ and 5‐year biopsies, mild fibrosis present at 1 year progressed to more severe forms at 5 years in 23% of allografts. The prevalence of moderate or severe arteriolar hyalinosis was similar in tacrolimus and calcineurin inhibitor‐free immunosuppression. These results in the recent era of transplantation demonstrate fewer, less severe and less progressive chronic histologic changes in the first 5 years after transplantation than previously reported.
This study of protocol renal allograft biopsies suggests that chronic histologic changes at 5 years are less severe than previously reported, and that mild fibrosis present at 1 year does not commonly progress to more severe forms. See editorial by Brouard et al on page 647.
Objective Hypoxic-ischemic white mater brain injury commonly occurs in neonates with hypoplastic left heart syndrome (HLHS). Approximately one half of HLHS survivors will exhibit neurobehavioral ...symptoms believed to be associated with this injury, although the exact timing of the injury is unknown. Methods Neonates with HLHS were recruited for pre- and postoperative monitoring of cerebral oxygen saturation, cerebral oxygen extraction fraction, and cerebral blood flow using 2 noninvasive optical-based techniques: diffuse optical spectroscopy and diffuse correlation spectroscopy. Anatomic magnetic resonance imaging was performed before and approximately 1 week after surgery to quantify the extent and timing of the acquired white matter injury. The risk factors for developing new or worsened white matter injury were assessed using uni- and multivariate logistic regression. Results A total of 37 neonates with HLHS were studied. On univariate analysis, neonates who developed a large volume of new, or worsened, postoperative white matter injury had a significantly longer time to surgery ( P = .0003). In a multivariate model, a longer time between birth and surgery, delayed sternal closure, and greater preoperative cerebral blood flow were predictors of postoperative white matter injury. Additionally, a longer time to surgery and greater preoperative cerebral blood flow on the morning of surgery correlated with lower cerebral oxygen saturation ( P = .03 and P = .05, respectively) and greater oxygen extraction fraction ( P = .05 for both). Conclusions A longer time to surgery was associated with new postoperative white matter injury in otherwise healthy neonates with HLHS. The results suggest that earlier Norwood palliation might decrease the likelihood of acquiring postoperative white matter injury.
Hemodialysis arteriovenous access: Detection of stenosis and response to treatment by vascular access blood flow.
Hemodialysis access to the circulation is best provided by native and synthetic ...arteriovenous fistulae (AVF and AVG). Thromboses caused by venous outflow stenoses prevent the long-term use of AV access. This pilot study was performed to evaluate the ability of ultrasound dilution-derived access blood flows to detect AV access stenosis and to evaluate the response to treatment.
This pilot study was a single-center, prospective observational intervention trial. The monitoring technique used was ultrasound dilution access blood flow measurements performed monthly and after any intervention. Screening criteria for interventions were decrements in access flow of 20% when the flow value fell under 1000 mL/min or absolute flow of <600 mL/min. The primary intervention when flow criteria were met was biplanar venography of the access with percutaneous transluminal angioplasty (PTA) of detected stenoses. Stenoses unresponsive to PTA were sent for surgical revision. Access thrombosis was considered a study ending event.
Baseline access flow at study entry for AVF was 919 and 1237 mL/min for AVG. Sequential measurement of AV access flow detected AV access stenosis. PTA and surgical revision significantly restored AV access flow back toward the baseline flow measurement. Failure to restore access flow by at least 20% following intervention occurred in 14% of AVF and 21% of AVG PTA attempts. Transluminal angioplasty, once successfully performed, was required at a mean of 5.8-month intervals in order to maintain AVG flow. In contrast, AVF flow was restored for a much longer period of time following angioplasty (11.4 month follow-up at the time of study end). Compared with historic controls, which used venous dialysis pressure as the primary monitoring technique, the overall (AVF-AVG) thrombosis rates improved from 25 to 16% per patient year, and AVF thrombosis rates improved from 16 to 7% per patient year. When flow was not successfully restored, thrombosis ensued. Eight of 10 thrombosis episodes were predicted based on inability to improve access flow either as a result of stenosis treatment failure or unsuccessful referral for treatment.
Sequential measurement of AV access flow is an acceptable means of both monitoring for the development of access stenoses and assessing response to therapy. PTAs of AVF are more durable than PTAs of AV grafts.
Abstract Dietary and endogenous fatty acids could play a role in low-grade inflammation. In this cross-sectional study the proportions of erythrocyte membrane fatty acids (EMFA) and the ...concentrations of C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra) and adiponectin were measured and their confounder-adjusted associations examined in 1373 randomly selected Finnish men aged 45–70 years participating in the population based Metsim study in Eastern Finland. The sum of n −6 EMFAs, without linoleic acid (LA), was positively associated with concentrations of CRP and IL-1Ra ( rpartial =0.139 and rpartial =0.115, P <0.001). These associations were especially strong among lean men (waist circumference <94 cm; rpartial =0.156 and rpartial =0.189, P <0.001). Total n −3 EMFAs correlated inversely with concentrations of CRP ( rpartial =−0.098, P <0.001). Palmitoleic acid (16:1 n −7) correlated positively with CRP ( rpartial =0.096, P <0.001). Cis-vaccenic acid (18:1 n −7) was associated with high concentrations of adiponectin ( rpartial =0.139, P <0.001). In conclusion, n −6 EMFAs, except for LA, correlated positively with the inflammatory markers. Palmitoleic acid was associated with CRP, whereas, interestingly, its elongation product, cis-vaccenic acid, associated with anti-inflammatory adiponectin.
Reduction of CT tube current is an effective strategy to minimize radiation load. However, tube current is also a major determinant of image quality. We investigated the impact of CTA tube current on ...spot sign detection and diagnostic performance for intracerebral hemorrhage expansion.
We retrospectively analyzed a prospectively collected cohort of consecutive patients with primary intracerebral hemorrhage from January 2001 to April 2015 who underwent CTA. The study population was divided into 2 groups according to the median CTA tube current level: low current (<350 mA) and high current (≥350 mA). CTA first-pass readings for spot sign presence were independently analyzed by 2 readers. Baseline and follow-up hematoma volumes were assessed by semiautomated computer-assisted volumetric analysis. Sensitivity, specificity, positive and negative predictive values, and accuracy of spot sign in predicting hematoma expansion were calculated.
This study included 709 patients (288 and 421 in the low- and high-current groups, respectively). A higher proportion of low-current scans identified at least 1 spot sign (20.8% versus 14.7%,
= .034), but hematoma expansion frequency was similar in the 2 groups (18.4% versus 16.2%,
= .434). Sensitivity and positive and negative predictive values were not significantly different between the 2 groups. Conversely, high-current scans showed superior specificity (91% versus 84%,
= .015) and overall accuracy (84% versus 77%,
= .038).
CTA obtained at high levels of tube current showed better diagnostic accuracy for prediction of hematoma expansion by using spot sign. These findings may have implications for future studies using the CTA spot sign to predict hematoma expansion for clinical trials.
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