How much of the variance in functional outcome related to intracerebral hemorrhage volume is already apparent in neurological status at admission?

BACKGROUND: Hematoma volume is a major pathophysiological hallmark of acute intracerebral hemorrhage (ICH). We investigated how the variance in functional outcome induced by the ICH volume is explained by neurological deficits at admission using a mediation model. METHODS: Patients with acute ICH treated in three tertiary stroke centers between January 2010 and April 2019 were retrospectively analyzed. Mediation analysis was performed to investigate the effect of ICH volume (0.8 ml (5% quantile) versus 130.6 ml (95% quantile)) on the risk of unfavorable functional outcome at discharge defined as modified Rankin Score (mRS) ≥ 3 with mediation through National Institutes of Health Stroke Scale (NIHSS) at admission. Multivariable regression was conducted to identify factors related to neurological improvement and deterioration. RESULTS: Three hundred thirty-eight patients were analyzed. One hundred twenty-one patients (36%) achieved mRS ≤ 3 at discharge. Mediation analysis showed that NIHSS on admission explained 30% [13%; 58%] of the ICH volume-induced variance in functional outcome at smaller ICH volume levels, and 14% [4%; 46%] at larger ICH volume levels. Higher ICH volume at admission and brainstem or intraventricular location of ICH were associated with neurological deterioration, while younger age, normotension, lower ICH volumes, and lobar location of ICH were predictors for neurological improvement. CONCLUSION: NIHSS at admission reflects 14% of the functional outcome at discharge for larger hematoma volumes and 30% for smaller hematoma volumes. These results underscore the importance of effects not reflected in NIHSS admission for the outcome of ICH patients such as secondary brain injury and early rehabilitation.

Association of clinical outcome and imaging endpoints in extensive ischemic stroke-comparing measures of cerebral edema.

OBJECTIVES: Ischemic edema is associated with worse clinical outcomes, especially in large infarcts. Computed tomography (CT)-based densitometry allows direct quantification of absolute edema volume (EV), which challenges indirect biomarkers like midline shift (MLS). We compared EV and MLS as imaging biomarkers of ischemic edema and predictors of malignant infarction (MI) and very poor clinical outcome (VPCO) in early follow-up CT of patients with large infarcts. MATERIALS AND METHODS: Patients with anterior circulation stroke, large vessel occlusion, and Alberta Stroke Program Early CT Score (ASPECTS) ≤ 5 were included. VPCO was defined as modified Rankin scale (mRS) ≥ 5 at discharge. MLS and EV were quantified at admission and in follow-up CT 24 h after admission. Correlation was analyzed between MLS, EV, and total infarct volume (TIV). Multivariable logistic regression and receiver operating characteristics curve analyses were performed to compare MLS and EV as predictors of MI and VPCO. RESULTS: Seventy patients (median TIV 110 mL) were analyzed. EV showed strong correlation to TIV (r = 0.91, p < 0.001) and good diagnostic accuracy to classify MI (EV AUC 0.74 [95%CI 0.61-0.88] vs. MLS AUC 0.82 [95%CI 0.71-0.94]; p = 0.48) and VPCO (EV AUC 0.72 [95%CI 0.60-0.84] vs. MLS AUC 0.69 [95%CI 0.57-0.81]; p = 0.5) with no significant difference compared to MLS, which did not correlate with TIV < 110 mL (r = 0.17, p = 0.33). CONCLUSION: EV might serve as an imaging biomarker of ischemic edema in future studies, as it is applicable to infarcts of all volumes and predicts MI and VPCO in patients with large infarcts with the same accuracy as MLS. CLINICAL RELEVANCE STATEMENT: Utilization of edema volume instead of midline shift as an edema parameter would allow differentiation of patients with large and small infarcts based on the extent of edema, with possible advantages in the prediction of treatment effects, complications, and outcome. KEY POINTS: • CT densitometry-based absolute edema volume challenges midline shift as current gold standard measure of ischemic edema. • Edema volume predicts malignant infarction and poor clinical outcome in patients with large infarcts with similar accuracy compared to MLS irrespective of the lesion extent. • Edema volume might serve as a reliable quantitative imaging biomarker of ischemic edema in acute stroke triage independent of lesion size.

Quantification of ischemic brain edema after mechanical thrombectomy using dual-energy computed tomography in patients with ischemic stroke.

Net water uptake (NWU) is a quantitative imaging biomarker used to assess cerebral edema resulting from ischemia via Computed Tomography (CT)-densitometry. It serves as a strong predictor of clinical outcome. Nevertheless, NWU measurements on follow-up CT scans after mechanical thrombectomy (MT) can be affected by contrast staining. To improve the accuracy of edema estimation, virtual non-contrast images (VNC-I) from dual-energy CT scans (DECT) were compared to conventional polychromatic CT images (CP-I) in this study. We examined NWU measurements derived from VNC-I and CP-I to assess their agreement and predictive value in clinical outcome. 88 consecutive patients who received DECT as follow-up after MT were included. NWU was quantified on CP-I (cNWU) and VNC-I (vNWU). The clinical endpoint was functional independence at discharge. cNWU and vNWU were highly correlated (r = 0.71, p < 0.0001). The median difference between cNWU and vNWU was 8.7% (IQR: 4.5-14.1%), associated with successful vessel recanalization (mTICI2b-3) (ß: 11.6%, 95% CI 2.9-23.0%, p = 0.04), and age (ß: 4.2%, 95% CI 1.3-7.0%, p = 0.005). The diagnostic accuracy to classify outcome between cNWU and vNWU was similar (AUC:0.78 versus 0.77). Although there was an 8.7% median difference, indicating potential edema underestimation on CP-I, it did not have short-term clinical implications.

Comparison of Thrombolysis In Cerebral Infarction (TICI) 2b and TICI 3 reperfusion in endovascular therapy for large ischemic anterior circulation strokes.

BACKGROUND: Landmark thrombectomy trials have provided evidence that selected patients with large ischemic stroke benefit from successful endovascular therapy, commonly defined as incomplete (modified Thrombolysis In Cerebral Infarction (mTICI) 2b) or complete reperfusion (mTICI 3). We aimed to investigate whether mTICI 3 improves functional outcomes compared with mTICI 2b in large ischemic strokes. METHODS: This retrospective multicenter cohort study was conducted to compare mTICI 2b versus mTICI 3 in large ischemic strokes in the anterior circulation. Patients enrolled in the German Stroke Registry between 2015-2021 were analyzed. Large ischemic stroke was defined as an Alberta Stroke Program Early CT Score (ASPECTS) of 3-5. Patients were matched by final mTICI grade using propensity score matching. Primary outcome was the 90-day modified Rankin Scale (mRS) score. RESULTS: After matching, 226 patients were included. Baseline and imaging characteristics were balanced between mTICI 2b and mTICI 3 patients. There was no shift on the mRS favoring mTICI 3 compared with mTICI 2b in large ischemic strokes (adjusted common odds ratio (acOR) 1.12, 95% confidence interval (95% CI) 0.64 to 1.94, P=0.70). The rate of symptomatic intracranial hemorrhage was higher in mTICI 2b than in mTICI 3 patients (12.6% vs 4.5%, P=0.03). Mortality at 90 days did not differ between mTICI 3 and mTICI 2b (33.6% vs 37.2%; adjusted OR 0.69, 95% CI 0.33 to 1.45, P=0.33). CONCLUSIONS: In endovascular therapy for large ischemic strokes, mTICI 3 was not associated with better 90-day functional outcomes compared with mTICI 2b. This study suggests that mTICI 2b might be warranted as the final angiographic result, questioning the benefit/risk ratio of additional maneuvers to seek for mTICI 3 in large ischemic strokes. TRIAL REGISTRATION NUMBER: NCT03356392.

Association Between Recanalization Attempts and Functional Outcome After Thrombectomy for Large Ischemic Stroke.

BACKGROUND: Recently, 3 randomized controlled trials provided high-level evidence that patients with large ischemic stroke achieved better functional outcomes after endovascular therapy than with medical care alone. We aimed to investigate whether the clinical benefit of endovascular therapy is associated with the number of recanalization attempts in extensive baseline infarction. METHODS: This retrospective multicenter study enrolled patients from the German Stroke Registry who underwent endovascular therapy for anterior circulation large vessel occlusion between 2015 and 2021. Large ischemic stroke was defined as an Alberta Stroke Program Early Computed Tomography Score of 3 to 5. The study cohort was divided into patients with unsuccessful reperfusion (Thrombolysis in Cerebral Infarction score, 0-2a) and successful reperfusion (Thrombolysis in Cerebral Infarction score, 2b/3) at attempts 1, 2, 3, or ≥4. The primary outcome was favorable functional outcome defined as modified Rankin Scale score of 0 to 3 at 90 days. Safety outcomes were symptomatic intracranial hemorrhage after 24 hours and death within 90 days. Multivariable logistic regression was used to identify independent determinants of primary and secondary outcomes. RESULTS: A total of 348 patients met the inclusion criteria. Successful reperfusion was observed in 83.3% and favorable functional outcomes in 36.2%. Successful reperfusion at attempts 1 (adjusted odds ratio, 5.97 [95% CI, 1.71-24.43]; P=0.008) and 2 (adjusted odds ratio, 6.32 [95% CI, 1.73-26.92]; P=0.008) increased the odds of favorable functional outcome, whereas success at attempts 3 or ≥4 did not. Patients with >2 attempts showed higher rates of symptomatic intracranial hemorrhage (12.8% versus 6.5%; P=0.046). Successful reperfusion at any attempt lowered the odds of death compared with unsuccessful reperfusion. CONCLUSIONS: In patients with large vessel occlusion and Alberta Stroke Program Early Computed Tomography Score of 3 to 5, the clinical benefit of endovascular therapy was linked to the number of recanalization attempts required for successful reperfusion. Our findings encourage to perform at least 2 recanalization attempts to seek for successful reperfusion in large ischemic strokes, while >2 attempts should follow a careful risk-benefit assessment in these highly affected patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03356392.

Hypoperfusion Intensity Ratio Is Correlated With the Risk of Parenchymal Hematoma After Endovascular Stroke Treatment.

BACKGROUND: Parenchymal hematoma (PH) is a major complication after endovascular treatment (EVT) for ischemic stroke. The hypoperfusion intensity ratio (HIR) represents a perfusion parameter reflecting arterial collateralization and cerebral microperfusion in ischemic brain tissue. We hypothesized that HIR correlates with the risk of PH after EVT. METHODS: Retrospective multicenter cohort study of patients with large vessel occlusion who underwent EVT between 2013 and 2021 at one of the 2 comprehensive stroke centers (University Medical Center Hamburg-Eppendorf, Germany and Stanford University School of Medicine, CA). HIR was automatically calculated on computed tomography perfusion studies as the ratio of brain volume with time-to-max (Tmax) delay >10 s over volume with Tmax >6 s. Reperfusion hemorrhages were assessed according to the Heidelberg Bleeding Classification. Primary outcome was PH occurrence (PH+) or absence (PH-) on follow-up imaging. Secondary outcome was good clinical outcome defined as a 90-day modified Rankin Scale score of 0 to 2. RESULTS: A total of 624 patients met the inclusion criteria. We observed PH in 91 (14.6%) patients after EVT. PH+ patients had higher HIR on admission compared with PH- patients (median, 0.6 versus 0.4; P<0.001). In multivariable regression, higher admission blood glucose (adjusted odds ratio [aOR], 1.08 [95% CI, 1.04-1.13]; P<0.001), extensive baseline infarct defined as Alberta Stroke Program Early CT Score ≤5 (aOR, 2.48 [1.37-4.42]; P=0.002), and higher HIR (aOR, 1.22 [1.09-1.38]; P<0.001) were independent determinants of PH after EVT. Both higher HIR (aOR, 0.83 [0.75-0.92]; P<0.001) and PH on follow-up imaging (aOR, 0.39 [0.18-0.80]; P=0.013) were independently associated with lower odds of achieving good clinical outcome. CONCLUSIONS: Poorer (higher) HIR on admission perfusion imaging was strongly associated with PH occurrence after EVT. HIR as a surrogate for cerebral microperfusion might reflect tissue vulnerability for reperfusion hemorrhages. This automated and quickly available perfusion parameter might help to assess the need for intensive medical care after EVT.

Continuing early mTICI 2b recanalization may improve functional outcome but is associated with a higher risk of intracranial hemorrhage.

Background: Successful reperfusion (mTICI 2c/3) and low number of passes are key determinants for good clinical outcome in acute large vessel occlusion. While final mTICI 2c/3 reperfusion is superior to partial reperfusion (mTICI 2b) it remains unclear if this is also true for the subgroup of patients with early mTICI 2b (achieved in ≤2 retrieval attempts) reperfusion who are secondarily improved to mTICI 2c/3. This study was designed to examine if early mTICI2b should be continued or stopped during mechanical thrombectomy (MT). Methods: Nine hundred and thirteen ischemic stroke patients who received MT were retrospectively analyzed. Angiography runs following each recanalization attempt were scored for mTICI. The patients with early mTICI 2b reperfusions were dichotomized in "TICI2b-stopped" (MT withdrawal after mTICI 2b was achieved with first or second retrieval) and "TICI2b-continued" (MT was continued after mTICI 2b was achieved with first or second retrieval). Functional outcome was obtained after 90 days using the modified Rankin scale (mRS90). Results: Of 362 Patients with a M1-occlusion, 100 patients fulfilled the inclusion criteria with an early mTICI 2b. 78/100 patients were included in the "TICI2b-stopped" group and 22/100 patients were in the "TICI2b-continued" group. Of these 22 patients, none had a final mTICI score lower than 2b and 11 patients had a final mTICI score of 2c/3. Regarding good functional outcome at mRS90, "TICI2b-continued" showed by trend a slight advantage of 40.1 vs. 35.6% in "TICI2b-stopped" but in multivariate logistic regression analysis adjusted for confounders, no significant difference was found between the two groups (OR 0.75, 95% CI 0.19-2.87, p = 0.67). Symptomatic intracranial hemorrhage was significantly higher in "TICI2b-continued" compared to "TICI2b-stopped" (31.8 vs. 10.3%, p = 0.031). Conclusion: Successfully improving an early mTICI 2b to mTICI 2c/3 reperfusion is possible in a substantial number of patients and might improve functional outcome. However, an increase in symptomatic intracranial hemorrhage (SICH) due to further retrieval attempts may diminish the potential functional benefit to continue early mTICI 2b. To support this finding, further investigation with more power is needed to account for the low number of events regarding SICH.

Single-Center Retrospective Comparative Study Evaluating the Benefit of Computed Tomography Angiography Prior to Prostatic Artery Embolization.

PURPOSE: To explore whether a computed tomography angiography (CTA) of the pelvis prior to prostatic artery embolization (PAE) is a beneficial preprocedural planning tool regarding the technical success. MATERIALS AND METHODS: Eighty patients with lower urinary tract symptoms treated with PAE were analyzed retrospectively. Forty of these patients received a CTA of the pelvis prior to the procedure (Group A) and were compared to 40 patients who were treated with PAE without prior CT imaging (Group B). Technical success rate, rate of complications, fluoroscopy time (FT), and mean dose area product (DAP) were assessed and compared. All operators performed at least 50 PAE prior to this study. When needed, cone-beam CT (CBCT) was available during intervention. RESULTS: Mean age was 68.43 ± 8.30 years in Group A and 70.42 ± 7.11 years in Group B (p = 0.252). Mean body mass index was 26.78 ± 3.73 in Group A and 26.85 ± 3.5 in Group B (p = 0.319). Overall technical success was 96.3%. Bilateral PAE was achieved in 60 patients (75.0%) while unilateral PAE was performed in 17 patients (21.3%). Technical failure (no embolization) occurred in two patients of Group A and one patient of Group B. No statistical significance was seen between groups for technical success rate (p = 1.0). Mean DAP was 10,164 × cm2 ± 3944 cGy × cm2 in Group A and 10,039 × cm2 ± 3761 cGy × cm2 in Group B (p = 0.885). Mean FT was 49.27 ± 22.97 min in Group A and 44.32 ± 17.82 min in Group B (p = 0.285). No intervention-related complications during PAE were reported. CONCLUSION: With experienced interventionalists and CBCT available during PAE, preprocedural CTA has no additional benefit for technical outcome.

Meniscus Injury and its Surgical Treatment Does not Increase Initial Whole Knee Joint Friction.

While it is generally accepted that traumatic meniscus pathologies lead to degenerative articular cartilage changes in the mid-to long-term and consecutively to post-traumatic osteoarthritis (PTOA), very little is known about how such injuries initiate tribological changes within the knee and their possible impact on PTOA acceleration. Therefore, the aim of this study was to investigate the influence of three different medial meniscus states (intact, posterior root tear, total meniscectomy) on the initial whole knee joint friction. Six ovine knee joints were tested in a passive pendulum friction testing device under an axial load of 250 N and an initial deflection of 12°, representing swing phase conditions, and under an axial load of 1000 N and an initial deflection of 5°, simulating stance phase conditions. To additionally consider the influence of the time-dependent viscoelastic nature of the knee joint soft tissues on whole joint friction, the tests were performed twice, directly following load application and after 20 min creep loading of either 250 N or 1000 N axial load. On the basis of a three-dimensional joint kinematic analysis, the energy loss during the passive joint motion was analyzed, which allowed considerations on frictional and damping processes within the joint. The so-called "whole knee joint" friction was evaluated using the boundary friction model from Stanton and a viscous friction model from Crisco et al., both analyzing the passive joint flexion-extension motion in the sagittal plane. Significantly lower friction coefficients were observed in the simulated swing phase after meniscectomy (p < 0.05) compared to the intact state. No initial whole joint friction differences between the three meniscus states (p > 0.05) were found under stance phase conditions. Soft tissue creeping significantly increased all the determined friction coefficients (p < 0.05) after resting under load for 20 min. The exponential decay function of the viscous friction model provided a better fit (R 2∼0.99) to the decaying flexion-extension data than the linear decay function of the boundary friction model (R 2∼0.60). In conclusion, this tribological in vitro study on ovine knee joints indicated that neither a simulated posterior medial meniscus root tear nor the removal of the medial meniscus resulted in an initially increased whole joint friction.

Value of Dual-Energy Dual-Layer CT After Mechanical Recanalization for the Quantification of Ischemic Brain Edema.

Background and Purpose: Ischemic brain edema can be measured in computed tomography (CT) using quantitative net water uptake (NWU), a recently established imaging biomarker. NWU determined in follow-up CT after mechanical thrombectomy (MT) has shown to be a strong predictor of functional outcome. However, disruption of the blood-brain barrier after MT may also lead to contrast staining, increasing the density on CT scans, and hence, directly impairing measurements of NWU. The purpose of this study was to determine whether dual-energy dual-layer CT (DDCT) after MT can improve the quantification of NWU by measuring NWU in conventional polychromatic CT images (CP-I) and virtual non-contrast images (VNC-I). We hypothesized that VNC-based NWU (vNWU) differs from NWU in conventional CT (cNWU). Methods: Ten patients with middle cerebral artery occlusion who received a DDCT follow-up scan after MT were included. NWU was quantified in conventional and VNC images as previously published and was compared using paired sample t-tests. Results: The mean cNWU was 3.3% (95%CI: 0-0.41%), and vNWU was 11% (95%CI: 1.3-23.4), which was not statistically different (p = 0.09). Two patients showed significant differences between cNWU and vNWU (Δ = 24% and Δ = 36%), while the agreement of cNWU/vNWU in 8/10 patients was high (difference 2.3%, p = 0.23). Conclusion: NWU may be quantified precisely on conventional CT images, as the underestimation of ischemic edema due to contrast staining was low. However, a proportion of patients after MT might show significant contrast leakage resulting in edema underestimation. Further research is needed to validate these findings and investigate clinical implications.

Improved Detectability of Brain Stem Ischemia by Combining Axial and Coronal Diffusion-Weighted Imaging.

BACKGROUND AND PURPOSE: To evaluate the benefit of a coronal diffusion-weighted imaging (DWI) in addition to standard axial DWI for the detection of brain stem infarctions. METHODS: A retrospective analysis of patients with symptoms consistent with acute and subacute brain stem infarction who received magnetic resonance imaging, including axial and coronal DWI. Diffusion restrictions were identified by 2 independent raters blinded for the final clinical diagnosis in 3 separate reading steps: axial DWI, coronal DWI, and combined axial and coronal DWI. Lesion location and certainty level were both documented for each reading step. In cases of reader disagreement, an additional consensus reading was performed. RESULTS: Two hundred thirty-nine patients were included. Of these, 124 patients (51.9%) were clinically diagnosed with brain stem infarction. Sensitivity, specificity, positive, and negative predictive values were best for combined DWI assessment (90.3%, 99.1%, 99.1%, and 90.5%) compared with axial (85.5%, 94.9%, 94.6%, and 85.8%) and coronal DWI alone (87.9%, 96.5%, 96.5%, and 88.1%). Diffusion restriction on combined DWI was diagnosed in 112/124 patients compared with 106/124 on axial DWI and 109/124 on coronal DWI. Interobserver agreement for the detection of brain stem lesions was the highest in the combined rating step (Cohen κ coefficient=0.94). CONCLUSIONS: Coronal DWI sequences might improve the detection rate of brain stem infarction compared with standard axial DWI. The combined coronal and axial DWI provides the best detection rate while minimally increasing scan times.

Forces at the Anterior Meniscus Attachments Strongly Increase Under Dynamic Knee Joint Loading.

BACKGROUND: The anatomic appearance and biomechanical and clinical importance of the anterior meniscus roots are well described. However, little is known about the loads that act on these attachment structures under physiological joint loads and movements. HYPOTHESES: As compared with uniaxial loading conditions under static knee flexion angles or at very low flexion-extension speeds, more realistic continuous movement simulations in combination with physiological muscle force simulations lead to significantly higher anterior meniscus attachment forces. This increase is even more pronounced in combination with a longitudinal meniscal tear or after total medial meniscectomy. STUDY DESIGN: Controlled laboratory study. METHODS: A validated Oxford Rig-like knee simulator was used to perform a slow squat, a fast squat, and jump landing maneuvers on 9 cadaveric human knee joints, with and without muscle force simulation. The strains in the anterior medial and lateral meniscal periphery and the respective attachments were determined in 3 states: intact meniscus, medial longitudinal tear, and total medial meniscectomy. To determine the attachment forces, a subsequent in situ tensile test was performed. RESULTS: Muscle force simulation resulted in a significant strain increase at the anterior meniscus attachments of up to 308% (P < .038) and the anterior meniscal periphery of up to 276%. This corresponded to significantly increased forces (P < .038) acting in the anteromedial attachment with a maximum force of 140 N, as determined during the jump landing simulation. Meniscus attachment strains and forces were significantly influenced (P = .008) by the longitudinal tear and meniscectomy during the drop jump simulation. CONCLUSION: Medial and lateral anterior meniscus attachment strains and forces were significantly increased with physiological muscle force simulation, corroborating our hypothesis. Therefore, in vitro tests applying uniaxial loads combined with static knee flexion angles or very low flexion-extension speeds appear to underestimate meniscus attachment forces. CLINICAL RELEVANCE: The data of the present study might help to optimize the anchoring of meniscal allografts and artificial meniscal substitutes to the tibial plateau. Furthermore, this is the first in vitro study to indicate reasonable minimum stability requirements regarding the reattachment of torn anterior meniscus roots.

Sex-specific Difference of Hippocampal Synaptic Plasticity in Response to Sex Neurosteroids.

Numerous studies provide increasing evidence, which supports the ideas that every cell in the brain of males may differ from those in females due to differences in sex chromosome complement as well as in response to hormonal effects. In this study, we address the question as to whether actions of neurosteroids, thus steroids, which are synthesized and function within the brain, contribute to sex-specific hippocampal synaptic plasticity. We have previously shown that predominantly in the female hippocampus, does inhibition of the conversion of testosterone to estradiol affect synaptic transmission. In this study, we show that testosterone and its metabolite dihydrotestosterone are essential for hippocampal synaptic transmission specifically in males. This also holds true for the density of mushroom spines and of spine synapses. We obtained similar sex-dependent results using primary hippocampal cultures of male and female animals. Since these cultures originated from perinatal animals, our findings argue for sex-dependent differentiation of hippocampal neurons regarding their responsiveness to sex neurosteroids up to birth, which persist during adulthood. Hence, our in vitro findings may point to a developmental effect either directly induced by sex chromosomes or indirectly by fetal testosterone secretion during the perinatal critical period, when developmental sexual priming takes place.

Do Prophylactic Knee Braces Protect the Knee Against Impacts or Tibial Moments? An In Vitro Multisensory Study.

BACKGROUND: Knee braces are prescribed by physicians to protect the knee from various loading conditions during sports or after surgery, even though the effect of bracing for various loading scenarios remains unclear. PURPOSE: To extensively investigate whether bracing protects the knee against impacts from the lateral, medial, anterior, or posterior directions at different heights as well as against tibial moments. STUDY DESIGN: Controlled laboratory study. METHODS: Eight limb specimens were exposed to (1) subcritical impacts from the medial, lateral, anterior, and posterior directions at 3 heights (center of the joint line and 100 mm inferior and superior) and (2) internal/external torques. Using a prophylactic brace, both scenarios were conducted under braced and unbraced conditions with moderate muscle loads and intact soft tissue. The change in anterior cruciate ligament (ACL) strain, joint acceleration in the tibial and femoral bones (for impacts only), and joint kinematics were recorded and analyzed. RESULTS: Bracing reduced joint acceleration for medial and lateral center impacts. The ACL strain change was decreased for medial superior impacts and increased for anterior inferior impacts. Impacts from the posterior direction had substantially less effect on the ACL strain change and joint acceleration than anterior impacts. Bracing had no effect on the ACL strain change or kinematics under internal or external moments. CONCLUSION: Our results indicate that the effect of bracing during impacts depends on the direction and height of the impact and is partly positive, negative, or neutral and that soft tissue absorbs impact energy. An effect during internal or external torque was not detected. CLINICAL RELEVANCE: Bracing in contact sports with many lateral or medial impacts might be beneficial, whereas athletes who play sports with rotational moments on the knee or anterior impacts may be safer without a brace.

rac-(6S)-6-Hy-droxy-6-{2-[2-(propan-2-yl-idene)hydrazinyl-idene]prop-yl}indolo[2,1-b]quinazolin-12(6H)-one.

The chiral title compound, C(21)H(20)N(4)O(2), crystallizes as a racemic mixture. In the crystal, mol-ecules form centrosymmetric π-overlapping dimers [inter-planar distance = 3.338 (6) Å], which are further connected along the a axis forming centrosymmetric dimers via O-H⋯N hydrogen bonds. C-H⋯O inter-actions are also observed. The indolo[2,1-b]quinazoline group is somewhat bent, with a small dihedral angle of 6.3 (4)° between the plane of the quinazoline system and the plane of the benzene ring of the indole moiety. The C=N-N=C atoms of the azine group is oriented almost perpendicular [84.1 (2)°] to the mean plane of the quinazoline system.

NOS inhibition synchronizes calcium oscillations in human adipose tissue-derived mesenchymal stem cells by increasing gap-junctional coupling.

Adipose tissue-derived mesenchymal stem cells (ASCs) are a promising stem cell source for cell transplantation. We demonstrate that undifferentiated ASCs display robust oscillations of intracellular calcium [Ca(2+) ](i) which may be associated with stem cell maintenance since oscillations were absent in endothelial cell differentiation medium supplemented with FGF-2. [Ca(2+) ](i) oscillations were dependent on extracellular Ca(2+) and Ca(2+) release from intracellular stores since they were abolished in Ca(2+) -free medium and in the presence of the store-depleting agent thapsigargin. They were inhibited by the phospholipase C antagonist U73,122, the inositol 1,4,5-trisphosphate (InsP(3) ) receptor antagonist 2-aminoethoxydiphenyl borate (2-APB) as well as by the gap-junction uncouplers 1-heptanol and carbenoxolone, indicating regulation by the InsP(3) pathway and dependence on gap-junctional coupling. Cells endogenously generated nitric oxide (NO), expressed NO synthase 1 (NOS 1) and connexin 43 (Cx 43). The nitric oxide NOS inhibitors NG-monomethyl-L-arginine (L-NMMA), N(G)-nitro-L-arginine methyl ester (L-NAME), 2-ethyl-2-thiopseudourea, and diphenylene iodonium as well as si-RNA-mediated down-regulation of NOS 1 synchronized [Ca(2+) ](i) oscillations between individual cells, whereas the NO-donors S-nitroso-N-acetylpenicillamine (SNAP) and sodium nitroprusside (SNP) as well as the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) were without effects. The synchronization of [Ca(2+) ](i) oscillations was due to an improvement of intracellular coupling since fluorescence recovery after photobleaching (FRAP) revealed increased reflow of fluorescent calcein into the bleached area in the presence of the NOS inhibitors DPI and L-NAME. In summary our data demonstrate that intracellular NO levels regulate synchronization of [Ca(2+) ](i) oscillations in undifferentiated ASCs by controlling gap-junctional coupling.