Endothelial FOXC1 and FOXC2 promote intestinal regeneration after ischemia-reperfusion injury.

Intestinal ischemia underlies several clinical conditions and can result in the loss of the intestinal mucosal barrier. Ischemia-induced damage to the intestinal epithelium is repaired by stimulation of intestinal stem cells (ISCs), and paracrine signaling from the vascular niche regulates intestinal regeneration. Here, we identify FOXC1 and FOXC2 as essential regulators of paracrine signaling in intestinal regeneration after ischemia-reperfusion (I/R) injury. Vascular endothelial cell (EC)- and lymphatic EC (LEC)-specific deletions of Foxc1, Foxc2, or both in mice worsen I/R-induced intestinal damage by causing defects in vascular regrowth, expression of chemokine CXCL12 and Wnt activator R-spondin 3 (RSPO3) in blood ECs (BECs) and LECs, respectively, and activation of Wnt signaling in ISCs. Both FOXC1 and FOXC2 directly bind to regulatory elements of the CXCL12 and RSPO3 loci in BECs and LECs, respectively. Treatment with CXCL12 and RSPO3 rescues the I/R-induced intestinal damage in EC- and LEC-Foxc mutant mice, respectively. This study provides evidence that FOXC1 and FOXC2 are required for intestinal regeneration by stimulating paracrine CXCL12 and Wnt signaling.

FOXC1 and FOXC2 Ablation Causes Abnormal Valvular Endothelial Cell Junctions and Lymphatic Vessel Formation in Myxomatous Mitral Valve Degeneration.

BACKGROUND: Mitral valve (MV) disease including myxomatous degeneration is the most common form of valvular heart disease with an age-dependent frequency. Genetic evidence indicates that mutations of the transcription factor FOXC1 are associated with MV defects, including MV regurgitation. In this study, we sought to determine whether murine Foxc1 and its closely related factor, Foxc2, are required in valvular endothelial cells (VECs) for the maintenance of MV leaflets, including VEC junctions and the stratified trilaminar ECM (extracellular matrix). METHODS: Adult mice carrying tamoxifen-inducible, vascular endothelial cell (EC), and lymphatic EC-specific, compound Foxc1;Foxc2 mutations (ie, EC-Foxc-DKO and lymphatic EC-Foxc-DKO mice, respectively) were used to study the function of Foxc1 and Foxc2 in the maintenance of MVs. The EC and lymphatic EC mutations of Foxc1/c2 were induced at 7 to 8 weeks of age by tamoxifen treatment, and abnormalities in the MVs of these mutant mice were assessed via whole-mount immunostaining, immunohistochemistry/RNAscope, Movat pentachrome/Masson Trichrome staining, and Evans blue injection. RESULTS: EC deletions of Foxc1 and Foxc2 in mice resulted in abnormally extended and thicker MVs by causing defects in the regulation of ECM organization with increased proteoglycan and decreased collagen. Notably, reticular adherens junctions were found in VECs of control MV leaflets, and these reticular structures were severely disrupted in EC-Foxc-DKO mice. PROX1 (prospero homeobox protein 1), a key regulator in a subset of VECs on the fibrosa side of MVs, was downregulated in EC-Foxc1/c2 mutant VECs. Furthermore, we determined the precise location of lymphatic vessels in murine MVs, and these lymphatic vessels were aberrantly expanded and dysfunctional in EC-Foxc1/c2 mutant MVs. Lymphatic EC deletion of Foxc1/c2 also resulted in similar structural/ECM abnormalities as seen in EC-Foxc1/c2 mutant MVs. CONCLUSIONS: Our results indicate that Foxc1 and Foxc2 are required for maintaining the integrity of the MV, including VEC junctions, ECM organization, and lymphatic vessel formation/function to prevent myxomatous MV degeneration.

Regulation of cerebrovascular compliance compared with forearm vascular compliance in humans: a pharmacological study.

Increasing evidence indicates that cerebrovascular compliance contributes to the dynamic regulation of cerebral blood flow but the mechanisms regulating cerebrovascular compliance in humans are unknown. This retrospective study investigated the impact of neural, endothelial, and myogenic mechanisms on the regulation of vascular compliance in the cerebral vascular bed compared with the forearm vascular bed. An index of vascular compliance (Ci) was assessed using a Windkessel model applied to blood pressure waveforms (finger photoplethysmography) and corresponding middle cerebral artery blood velocity or brachial artery blood velocity waveforms (Doppler ultrasound). Data were analyzed during a 5-min baseline period (10 waveforms) under control conditions and during distinct sympathetic blockade (experiment 1, phentolamine; 10 adults), cholinergic blockade (experiment 2, glycopyrrolate; 9 adults), and myogenic blockade (experiment 3, nicardipine; 14 adults). In experiment 1, phentolamine increased Ci similarly in the cerebral vascular bed (131 ± 135%) and forearm vascular bed (93 ± 75%; P = 0.45). In experiment 2, glycopyrrolate increased cerebrovascular Ci (72 ± 61%) and forearm vascular Ci (74 ± 64%) to a similar extent (P = 0.88). In experiment 3, nicardipine increased Ci but to a greater extent in the cerebral vascular bed (88 ± 88%) than forearm vascular bed (20 ± 45%; P = 0.01). Therefore, adrenergic, cholinergic, and myogenic mechanisms contribute to the regulation of cerebrovascular and forearm vascular compliance. However, myogenic mechanisms appear to exert more specific control over vascular compliance in the brain relative to the forearm.NEW & NOTEWORTHY Vascular compliance represents an important determinant in the dynamics and regulation of blood flow through a vascular bed. However, the mechanisms that regulate vascular compliance remain poorly understood. This study examined the impact of neural, endothelial, and myogenic mechanisms on cerebrovascular compliance compared with forearm vascular compliance. Distinct pharmacological blockade of α-adrenergic, endothelial muscarinic, and myogenic inputs altered cerebrovascular and forearm vascular compliance. These results further our understanding of vascular control and blood flow regulation in the brain.

Intracerebral Hemorrhage Segmentation on Noncontrast Computed Tomography Using a Masked Loss Function U-Net Approach.

OBJECTIVE: Intracerebral hemorrhage (ICH) volume is a strong predictor of outcome in patients presenting with acute hemorrhagic stroke. It is necessary to segment the hematoma for ICH volume estimation and for computerized extraction of features, such as spot sign, texture parameters, or extravasated iodine content at dual-energy computed tomography. Manual and semiautomatic segmentation methods to delineate the hematoma are tedious, user dependent, and require trained personnel. This article presents a convolutional neural network to automatically delineate ICH from noncontrast computed tomography scans of the head. METHODS: A model combining a U-Net architecture with a masked loss function was trained on standard noncontrast computed tomography images that were down sampled to 256 × 256 size. Data augmentation was applied to prevent overfitting, and the loss score was calculated using the soft Dice loss function. The Dice coefficient and the Hausdorff distance were computed to quantitatively evaluate the segmentation performance of the model, together with the sensitivity and specificity to determine the ICH detection accuracy. RESULTS: The results demonstrate a median Dice coefficient of 75.9% and Hausdorff distance of 2.65 pixels in segmentation performance, with a detection sensitivity of 77.0% and specificity of 96.2%. CONCLUSIONS: The proposed masked loss U-Net is accurate in the automatic segmentation of ICH. Future research should focus on increasing the detection sensitivity of the model and comparing its performance with other model architectures.

The Impact of Dual Antiplatelet Therapy Duration on Unruptured Aneurysm Occlusion After Flow Diversion: A Multicenter Study.

OBJECTIVE: Endoluminal flow diversion reduces blood flow into intracranial aneurysms, promoting thrombosis. Postprocedural dual antiplatelet therapy (DAPT) is necessary for the prevention of thromboembolic complications. The purpose of this study is to therefore assess the impact that the type and duration of DAPT has on aneurysm occlusion rates and iatrogenic complications after flow diversion. METHODS: A retrospective review of a multicenter aneurysm database was performed from 2012 to 2020 to identify unruptured intracranial aneurysms treated with single device flow diversion and ≥12-month follow-up. Clinical and radiologic data were analyzed with aneurysm occlusion as a function of DAPT duration serving as a primary outcome measure. RESULTS: Two hundred five patients underwent flow diversion with a single pipeline embolization device with 12.7% of treated aneurysms remaining nonoccluded during the study period. There were no significant differences in aneurysm morphology or type of DAPT used between occluded and nonoccluded groups. Nonoccluded aneurysms received a longer mean duration of DAPT (9.4 vs 7.1 months, P = 0.016) with a significant effect of DAPT duration on the observed aneurysm occlusion rate (F(2, 202) = 4.2, P = 0.016). There was no significant difference in the rate of complications, including delayed ischemic strokes, observed between patients receiving short (≤6 months) and prolonged duration (>6 months) DAPT (7.9% vs 9.3%, P = 0.76). CONCLUSIONS: After flow diversion, an abbreviated duration of DAPT lasting 6 months may be most appropriate before transitioning to low-dose aspirin monotherapy to promote timely aneurysm occlusion while minimizing thromboembolic complications.

The long non-coding RNA BBOX1 antisense RNA 1 is upregulated in polycystic ovary syndrome (PCOS) and suppresses the role of microRNA-19b in the proliferation of ovarian granulose cells : Short title: BBOX1 antisense RNA 1 in cell proliferation.

BACKGROUND: MicroRNA-19b (miR-19b) has been reported to be downregulated in polycystic ovary syndrome (PCOS), while its upstream regulators are unclear. We speculated that miR-19b could potentially form a binding relationship with BBOX1 antisense RNA 1 (BBOX1-AS1), a long non-coding RNA recognized for its critical role in ovarian cancer. Subsequently, we investigated into their interaction in PCOS. METHODS: The expression of miR-19b and BBOX1-AS1 in follicular fluid from both control women (n = 80) and women with PCOS (n = 80) was detected by RT-qPCR. Correlations were analyzed with Pearson' correlation coefficient. The binding of miR-19b to the wild-type (-wt) ad mutant (-mut) BBOX1-AS1 was determined by RNA-RNA pulldown assay. Their interactions were detected by overexpression assay. Bromodeoxyuridine (BrdU) assay was applied for proliferation analysis. RESULTS: BBOX1-AS1 was highly upregulated, while miR-19b was downregulated in PCOS. There was no close correlation across PCOS and the control samples. Consistently, they did not regulate the expression of each other in granulosa cells. However, BBOX1-AS1-wt, but not BBOX1-AS1-mut, could directly interact with miR-19b. BBOX1-AS1 suppressed the role of miR-19b in inhibiting granulosa cell proliferation. CONCLUSION: BBOX1-AS1 is highly upregulated in PCOS, and it may serve as an endogenous competing RNA for miR-19b to suppress its role in inhibiting granulosa cell proliferation. Our study suggested the role of BBOX1-AS1 as a potential target to treat PCOS.

Histone deacetylase SirE regulates development, DNA damage response and aflatoxin production in Aspergillus flavus.

Aspergillus flavus is a ubiquitous saprotrophic soil-borne pathogenic fungus that causes crops contamination with the carcinogen aflatoxins. Although sirtuin E (SirE) is known to be a NAD-dependent histone deacetylase involved in global transcriptional regulation. Its biological functions in A. flavus are not fully understood. To explore the effects of SirE, we found that SirE was located in the nucleus and increased the level of H3K56 acetylation. The ΔsirE mutant had the most severe growth defect in the sirtuin family. The RNA-Seq revealed that sirE was crucial for secondary metabolism production as well as genetic information process and oxidation-reduction in A. flavus. Further analysis revealed that the ΔsirE mutant increased aflatoxin production. Both the sirE deletion and H3K56 mutants were highly sensitive to DNA damage and oxidative stresses, indicating that SirE was required for DNA damage and redox reaction by the H3K56 locus. Furthermore, the ΔsirE mutant displayed high sensitivity to osmotic stress and cell wall stress, but they may not be associated with the H3K56. Finally, the catalytic activity site N192 of SirE was required for regulating growth, deacetylase function and aflatoxin production. Together, SirE is essential for histone deacetylation and biological function in A. flavus.

Cerebrovascular Neuroprotection after Acute Concussion in Adolescents.

OBJECTIVE: To assess acute cerebrovascular function in concussed adolescents (14-21 years of age), whether it is related to resting cerebral hemodynamics, and whether it recovers chronically. METHODS: Cerebral vasoreactivity and autoregulation, based on middle cerebral artery blood flow velocity, was assessed in 28 concussed participants (≤14 days of injury) and 29 matched controls. The participants in the concussion group returned for an 8-week follow-up assessment. Over the course of those 8-weeks, participants recorded aerobic exercise frequency and duration. RESULTS: Between groups, demographic, clinical, and hemodynamic variables were not significantly different. Vasoreactivity was significantly higher in the concussed group (p = 0.02). Within the concussed group, 60% of the variability in resting cerebral blood flow velocity was explained by vasoreactivity and two components of autoregulation - falling slope and effectiveness of autoregulation (adjusted R2  = 0.60, p < 0.001). Moreover, lower mean arterial pressure, lower responses to increases in arterial pressure, and lower vasoreactivity were significantly associated with larger symptom burden (adjusted R2  = 0.72, p < 0.01). By the 8-week timepoint, symptom burden, but not vasoreactivity, improved in all but four concussed participants (p < 0.01). 8-week change in vasoreactivity was positively associated with aerobic exercise volume (adjusted R2  = 0.19, p = 0.02). INTERPRETATION: Concussion resulted in changes in cerebrovascular regulatory mechanisms, which in turn explained the variability in resting cerebral blood flow velocity and acute symptom burden. Furthermore, these alterations persisted chronically despite symptom resolution, but was positively modified by aerobic exercise volume. These findings provide a mechanistic framework for further investigation into underlying cerebrovascular related symptomatology. ANN NEUROL 2021;90:43-51.

Intracranial Blood Flow Quantification by Accelerated Dual-venc 4D Flow MRI: Comparison With Transcranial Doppler Ultrasound.

BACKGROUND: Dual-venc 4D flow MRI, recently introduced for the assessment of intracranial hemodynamics, may provide a promising complementary approach to well-established tools such as transcranial Doppler ultrasound (TCD) and overcome some of their disadvantages. However, data comparing intracranial flow measures from dual-venc 4D flow MRI and TCD are lacking. PURPOSE: To compare cerebral blood flow velocity measures derived from dual-venc 4D flow MRI and TCD. STUDY TYPE: Prospective cohort. SUBJECTS: A total of 25 healthy participants (56 ± 4 years old, 44% female). FIELD STRENGTH/SEQUENCE: A 3 T/dual-venc 4D flow MRI using a time-resolved three-dimensional phase-contrast sequence with three-dimensional velocity encoding. ASSESSMENT: Peak velocity measurements in bilateral middle cerebral arteries (MCA) were quantified from dual-venc 4D flow MRI and TCD. The MRI data were quantified by two independent observers (S.M and Y.M.) and TCD was performed by a trained technician (A.L.M.). We assessed the agreement between 4D flow MRI and TCD measures, and the interobserver agreement of 4D flow MRI measurements. STATISTICAL TESTS: Peak velocity from MRI and TCD was compared using Bland-Altman analysis and coefficient of variance. Intraclass correlation coefficient (ICC) was used to assess MRI interobserver agreement. A P value < 0.05 was considered statistically significant. RESULTS: There was excellent interobserver agreement in dual-venc 4D flow MRI-based measurements of peak velocity in bilateral MCA (ICC = 0.97 and 0.96 for the left and right MCA, respectively). Dual-venc 4D flow MRI significantly underestimated peak velocity in the left and right MCA compared to TCD (bias = 0.13 [0.59, -0.33] m/sec and 0.15 [0.47, -0.17] m/sec, respectively). The coefficient of variance between dual-venc 4D flow MRI and TCD measurements was 26% for the left MCA and 22% for the right MCA. DATA CONCLUSION: There was excellent interobserver agreement for the assessment of MCA peak velocity using dual-venc 4D flow MRI, and ≤20% under-estimation compared with TCD. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Predictors of Acute Transfer and Mortality Within 6 Months From Admission to an Inpatient Rehabilitation Facility for Patients With Brain Tumors.

OBJECTIVE: To obtain useful information for clinicians in evaluating patients with brain tumors for transfer to and subsequent care in inpatient rehabilitation facilities (IRFs). DESIGN: Retrospective chart review. SETTING: Inpatient rehabilitation facility. PARTICIPANTS: A total of 208 adults with either initial or recurrent brain tumors who were admitted to an IRF between January 2017 and December 2018 after an acute hospitalization. INTERVENTIONS: None MAIN OUTCOME MEASURES: Transfer from an IRF to an acute care hospital and mortality within 6 months from admission to an IRF. RESULTS: Of the 208 patients who met inclusion criteria, 20.2% were transferred to an acute care hospital during the IRF stay, which was associated with prior chemotherapy, steroid use, and laterality of tumor. In total, 36.9% of patients with brain tumors died within 6 months of an IRF admission that was associated with recurrent tumor diagnosis, prior chemotherapy, prior neurosurgical intervention, prior neurostimulant use, use of steroids, isocitrate dehydrogenase and O6-methyl-guanyl-methyl-transferase biomarkers, and laterality and location of tumor. CONCLUSIONS: Patients with brain tumors have a notable potential for acute hospital transfer and mortality within 6 months of IRF stay, with several tumor- and treatment-related risk factors. This information can help identify functional goals, identify high risk patients, enable closer clinical monitoring, and facilitate focused care discussions at IRFs.

"All-in-one" window/level whole-body computed tomography scan - A faster way to evaluate trauma cases.

PURPOSE: To investigate the accuracy and total assessment time (TAT) of the "All-in-one" (AIO)-window/level setting for whole-body computed tomography (CT) image compared to multiple tissue-specific window/level settings conventionally used for detection of traumatic injuries. METHOD: Contrast-enhanced chest, abdomen, and pelvic CT scans of 50 patients who presented to our emergency department (ED) for major trauma were retrospectively selected. In a simulation of a "wet read" performed at the CT scanner console, 6 readers with different levels of experience had up to 3 min to describe any traumatic finding identified on the CTs. The readers reviewed each patient in two different sessions separated by a washout period to suppress any recall bias from one session to the next. Each scan was reviewed once using the AIO-window/level setting and another time using the conventional bone, lung, and soft tissue window/level display settings, in a randomized order. The CT reports were used as reference standard. RESULTS: Overall, there was no statistically significant difference in the assessment accuracy of the review based on the AIO or the conventional window/level settings (0.89 ± 0.09 vs 0.90 ± 0.08). Using the AIO-window/level settings, TAT was 14.3 s faster when compared with the conventional window/level settings (2.33 ± 0.63 vs 2.57 ± 0.51 min; p < 0.001). CONCLUSIONS: In a time-delimited image review, similar diagnostic accuracy was reached faster using the AIO vs the conventional window/level settings. When providing a "wet read" at the CT console, the ability to identify traumatic injury using a single AIO-window/level may help expedite patient management.

Postconcussion Exercise Volume Associations With Depression, Anxiety, and Dizziness Symptoms, and Postural Stability: Preliminary Findings.

OBJECTIVE: To examine the association between postconcussion exercise volume and changes in depression, anxiety, dizziness, and postural stability. DESIGN: Secondary analysis of a single-site prospective clinical trial. SETTING: Cerebrovascular research laboratory. PARTICIPANTS: Participants completed questionnaires and underwent tests of gait and balance within 2 weeks of a concussion (mean = 11 ± 3 days postconcussion) and approximately 1 month later (mean = 41 ± 7 days postconcussion). Exercise volume was tracked by weekly exercise logs. INTERVENTIONS: On the basis of a previous work classifying exercise volume following concussion, we grouped participants according to self-reported exercise volume between visits as high exercise volume (≥150 min/wk) or low exercise volume (<150 min/wk). MAIN OUTCOME MEASURES: Participants completed assessments evaluating anxiety and depression (Hospital Anxiety and Depression Scale), dizziness (Dizziness Handicap Inventory), and postural stability (tandem gait and modified Balance Error Scoring System). RESULTS: Thirty-eight participants completed the study, of which 22 were in the high exercise volume group (mean = 71 ± 40 min/wk; 16.8 ± 2.1 years; 59% female) and 16 were in the low exercise volume group (mean = 379 ± 187 min/wk; 17.5 ± 2.1 years; 31% female). Although depression symptoms were not significantly different initially (mean difference = 1.5; 95% CI, -0.68 to 3.68; P = .24), the high exercise volume group had significantly lower depression symptom scores at follow-up (mean difference = 3.0; 95% CI, 1.40 to 4.47; P < .001). Anxiety symptoms (mean difference = 2.8; 95% CI, 0.3 to 5.4; P = 0.03), dizziness symptoms (mean difference = 10.9; 95% CI, 0.2 to 21.5; P = .047), single-task tandem gait (mean difference = 3.1 seconds; 95% CI, 0.2 to 6.0; P = .04), and dual-task tandem gait (mean difference = 4.2 seconds; 95% CI, 0.2 to 8.2; P = .04) were significantly better among the high exercise volume group. CONCLUSION: Greater exercise volumes were associated with lower depression, anxiety, and dizziness symptoms, and faster tandem gait performance. These preliminary findings suggest a potentially beneficial role for exercise within several different domains commonly affected by concussion.

Clazosentan for Improvement of Time to Peak Perfusion in Patients with Angiographically Confirmed Severe Vasospasm.

BACKGROUND: Clazosentan, an endothelin-1 receptor antagonist, has been shown to prevent the development of large vessel angiographic vasospasm after aneurysmal subarachnoid hemorrhage. We hypothesized that clazosentan can improve cerebral perfusion for territories affected by angiographically confirmed vasospasm. METHODS: The REVERSE study (REversal of Vasospasm with clazosEntan post-aneuRysmal Subarachnoid hEmorrhage) was a prospective multicenter open-label pilot study of adult patients with aneurysmal subarachnoid hemorrhage who received intravenous clazosentan after developing moderate to severe angiographic vasospasm. Using the radiographic data from the REVERSE study and additional retrospective radiographic data from our tertiary medical center, we compared the impact of intravenous clazosentan with intraarterial vasodilator therapy (medical standard of care) on vasospasm reversal using time to peak perfusion (TTPP; the time interval between the peak opacification of contrast dye in the main artery supplying an anatomically defined territory and the parenchymal phase when the dye is diffusely present in the brain parenchyma). RESULTS: Both intravenous clazosentan (n = 7 vessels) and intraarterial vasodilator therapy (n = 11 vessels) resulted in a statistically significant improvement in TTPP at 24 h post intervention, when compared with the TTPP just prior to intervention for territories with angiographically confirmed severe vasospasm in the proximal arteries at baseline (linear mixed-effect model, p = 0.02). The clazosentan and intraarterial vasodilator therapy groups exhibited no statistically significant interaction term [time x treatment group (medical standard of care vs. clazosentan)] in our model (p = 0.71), suggesting similar temporal course of two therapies. CONCLUSIONS: In our small pilot study, intravenous clazosentan administered for at least 24 h had an effect comparable with that of intraarterial vasodilator therapy in reversing angiographically confirmed severe vasospasm. Our results may indicate that clazosentan, in an appropriately selected patient cohort, could offer a noninvasive approach for alleviating vasospasm.

Dizziness, Psychosocial Function, and Postural Stability Following Sport-Related Concussion.

OBJECTIVE: To examine if self-reported dizziness is associated with concussion symptoms, depression and/or anxiety symptoms, or gait performance within 2 weeks of postconcussion. DESIGN: Cross-sectional study. SETTING: Research laboratory. PARTICIPANTS: Participants were diagnosed with a concussion within 14 days of initial testing (N = 40). Participants were divided into 2 groups based on their Dizziness Handicap Inventory (DHI) score: 36 to 100 = moderate/severe dizziness and 0 to 35 = mild/no dizziness. INTERVENTIONS: Participants were tested on a single occasion and completed the DHI, hospital anxiety and depression scale (HADS), Patient Health Questionnaire-9 (PHQ-9), and Post-Concussion Symptom Inventory (PCSI). Three different postural control tests were use: modified Balance Error Scoring System, single-/dual-task tandem gait, and a single-/dual-task instrumented steady-state gait analysis. MAIN OUTCOME MEASURES: Comparison of patient-reported outcomes and postural control outcomes between moderate/severe (DHI ≥ 36) and mild/no (DHI < 36) dizziness groups. RESULTS: Participants with moderate/severe dizziness (n = 19; age = 17.1 ± 2.4 years; 63% female) reported significantly higher symptom burden (PSCI: 43.0 ± 20.6 vs 22.8 ± 15.7; P = 0.001) and had higher median HADS anxiety (6 vs 2; P < 0.001) and depression (6 vs 1; P = 0.001) symptom severity than those with no/minimal dizziness (n = 21; age = 16.5 ± 1.9; 38% female). During steady-state gait, moderate/severe dizziness group walked with significantly slower single-task cadence (mean difference = 4.8 steps/minute; 95% confidence interval = 0.8, 8.8; P = 0.02) and dual-task cadence (mean difference = 7.4 steps/minute; 95% confidence interval = 0.7, 14.0; P = 0.04) than no/mild dizziness group. CONCLUSION: Participants who reported moderate/severe dizziness reported higher concussion symptom burden, higher anxiety scores, and higher depression scores than those with no/mild dizziness. Cadence during gait was also associated with the level of dizziness reported.

Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis.

Increased endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) are the salient features of end-stage liver diseases. Using liver tissues from liver cirrhosis patients, we observed up-regulation of the XBP1-Hrd1 arm of the ER stress response pathway and down-regulation of the Nrf2-mediated antioxidant response pathway. We further confirmed this negative regulation of Nrf2 by Hrd1 using Hrd1 conditional knockout mice. Down-regulation of Nrf2 was a surprising result, since the high levels of ROS should have inactivated Keap1, the primary ubiquitin ligase regulating Nrf2 levels. Here, we identified Hrd1 as a novel E3 ubiquitin ligase responsible for compromised Nrf2 response during liver cirrhosis. In cirrhotic livers, activation of the XBP1-Hrd1 arm of ER stress transcriptionally up-regulated Hrd1, resulting in enhanced Nrf2 ubiquitylation and degradation and attenuation of the Nrf2 signaling pathway. Our study reveals not only the convergence of ER and oxidative stress response pathways but also the pathological importance of this cross-talk in liver cirrhosis. Finally, we showed the therapeutic importance of targeting Hrd1, rather than Keap1, to prevent Nrf2 loss and suppress liver cirrhosis.

Functional Gains Using Radial and Combined Shockwave Therapy in the Management of Achilles Tendinopathy.

Achilles tendinopathy is a common condition and many patients have functional limitations after initial conservative treatment. Shockwave therapy has been shown to improve function within patients; however, comparative outcomes for different forms of shockwave are poorly described. In this retrospective cohort study, we describe findings from a quality improvement initiative evaluating safety and functional outcomes after treatment with radial shockwave therapy (n = 58) or combined radial and focused shockwave therapy (n = 29) for patients with Achilles tendinopathy refractory to exercise therapy. All patients were prescribed an eccentric exercise program. We hypothesized both groups would see improvements in function quantified using the Victorian Institute of Sports Assessment-Achilles with similar safety outcomes. Overall, the minimal clinically important difference (defined at 7 for insertional and 12 for noninsertional Achilles tendinopathy) was met in a greater proportion of patients treated with combined shockwave compared to radial shockwave (26 [89.7%] vs 37 [63.8%], p = .022). The change in Victorian Institute of Sports Assessment-Achilles from baseline to final treatment was not different between combined and radial-only groups (23.3 ± 12.6 vs 19.9 ± 18.7, p = .2). Within group differences from baseline to final follow-up measures (mean duration 17.9 ± 14.8 weeks) demonstrated overall functional improvement for both groups (both p < .0001). No serious adverse effects were observed. Our findings suggest combined radial and focused shockwave therapy may provide more predictable functional gains for treatment of Achilles tendinopathy compared to radial shockwave therapy.

Rapid Assessment of Blood Pressure Variability and Outcome After Successful Thrombectomy.

BACKGROUND AND PURPOSE: High blood pressure (BP) variability after endovascular stroke therapy is associated with poor outcome. Conventional BP variability measures require long recordings, limiting their utility as a risk assessment tool to guide clinical decision-making. Here, we performed rapid assessment of BP variability by spectral analysis and evaluated its association with early clinical improvement and long-term functional outcomes. METHODS: We conducted a prospective study of 146 patients with anterior circulation ischemic stroke who underwent successful endovascular stroke therapy. Spectral analysis of 5-minute recordings of beat-to-beat BP was used to quantify BP variability. Outcomes included initial clinical response and modified Rankin Scale at 90 days. RESULTS: Increased BP variability at high frequencies was independently associated with poor functional outcome at 90 days (adjusted odds ratio [aOR], 1.85 [95% CI, 1.07-3.25], P=0.03; low-/high-frequency ratio aOR, 0.67 [95% CI, 0.46-0.92], P=0.02) and reduced likelihood of an early neurological recovery (aOR, 0.62 [95% CI, 0.44-0.91], P=0.01 and aOR, 1.37 [95% CI, 1.03-1.87], P=0.04, respectively). CONCLUSIONS: High-frequency BP oscillations after successful reperfusion may be harmful and associate with a decreased likelihood of neurological recovery and favorable functional outcomes. Rapid assessment of BP variability throughout the postreperfusion period is feasible and may allow for a more personalized BP management.

Ras subfamily GTPases regulate development, aflatoxin biosynthesis and pathogenicity in the fungus Aspergillus flavus.

Ras subfamily proteins are molecular switches in signal transduction pathways of many eukaryotes that regulate a variety of cellular processes. Here, the Ras subfamily, encoded by six genes, was identified in Aspergillus flavus: rasA, rasB, rasC, rab-33, rheb and rsr1. The rsr1 deletion mutant (∆rsr1), rheb deletion mutant (∆rheb) and double deletion mutant (∆rheb/rsr1) displayed significantly decreased growth and sporulation. Sclerotia formation was significantly decreased for ∆rheb or ∆rheb/rsr1 but increased for ∆rsr1. Aflatoxin production was significantly increased in ∆rheb but decreased in ∆rsr1 and ∆rheb/rsr1. We found that rsr1 and rheb are crucial for the pathogenicity of A. flavus. Quantitative proteomics identified 520 differentially expressed proteins (DEPs) for the ∆rsr1 mutant and 133 DEPs for the ∆rheb mutant. These DEPs were annotated in multiple biological processes and KEGG pathways in A. flavus. Importantly, we identified the cytokinesis protein SepA in the protein-protein interaction network of rsr1, and deletion mutants showed that SepA has pleiotropic effects on growth and AF biosynthesis, which may depend on Rsr1 for regulation in A. flavus. Our results indicated that these Ras subfamily proteins exhibited functional redundancy with each other but there were also differences in A. flavus.

Similar Functional Gains Using Radial Versus Combined Shockwave Therapy in Management of Plantar Fasciitis.

Plantar fasciitis is a common condition that causes foot pain. While shockwave therapy has been shown to provide successful results, comparative outcomes from different forms of shockwave therapy have yet to be described for this condition. In this retrospective cohort study, we describe findings from a quality improvement initiative assessing safety and functional outcomes for patients with plantar fasciitis treated with radial shockwave therapy (n = 20) or radial and focused shockwave therapy (combined shockwave, n = 18). Most were runners (n = 31, 81.6%), mean age was 43.3 ± 12.9 years, and average symptom duration 12.1 ± 11.1 months. All patients were prescribed an exercise program focusing on foot intrinsic strengthening. We hypothesized both groups would have improvement in function using the foot and Ankle Ability Measure, with a similar safety profile. Both radial and combined groups received similar number of total treatments (4.9 ± 2.5 and 4.1 ± 2.4, respectively; p = .33). Within group score changes for the Activities of Daily Living and Sports subscales were observed for both the radial (16.5 ± 16.3, p < .001; 31.7 ± 23.1, p < .001) and combined groups (19.8 ± 10.8, p = .001; 26.0 ± 21.5, p = .003). There was no difference in proportion of patients meeting the minimal clinically important difference between radial and combined groups regarding the Activities of Daily Living (14 (70%) vs 14 (77.8%), p = .58) and Sports subscales (17 (85%) vs 12 (75%), p = .45). Collectively, these findings suggest that a majority of patients with chronic plantar fasciitis may achieve functional gains using either form of shockwave therapy.

A Cell Wall Integrity-Related MAP Kinase Kinase Kinase AflBck1 Is Required for Growth and Virulence in Fungus Aspergillus flavus.

Aspergillus flavus represents an important fungal pathogen, causing severe economic losses in crops. The mitogen-activated protein (MAP) kinase signaling pathway contributes to many physiological processes, but its precise role in A. flavus is not yet fully understood. In this study, we focused on the AflBck1 gene, which encodes a MAP kinase kinase kinase of the Slt2-MAPK pathway. Targeted deletion of AflBck1 led to a significant defect in growth and development, and a AflBck1-deleted mutant (∆AflBck1) showed higher sensitivity to cell-wall stress than wild type (WT). Importantly, we observed that ∆AflBck1 displayed an enhanced ability to produce aflatoxin, a potential carcinogenic mycotoxin. However, the pathogenicity of the ∆AflBck1 mutant was markedly reduced in peanut seeds. We also presented evidence that AflBck1 was genetically epistatic to AflMkk2 in the Slt2-MAPK pathway. Finally, we found that loss of the proline-rich region at the N terminus of AflBck1 affected the reproduction of A. flavus. Collectively, this study not only extended the understanding that the MAPK pathway regulated A. flavus pathogenicity but also provided a possible strategy to control A. flavus contamination.