Mas receptor activation facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating neurological disease causing severe sensorimotor dysfunction and cognitive decline, yet there is no effective treatment strategy to alleviate outcomes of these patients. The Mas axis-mediated neuroprotection is involved in the pathology of various neurological diseases, however, the role of the Mas receptor in the setting of ICH remains to be elucidated. METHODS: C57BL/6 mice were used to establish the ICH model by injection of collagenase into mice striatum. The Mas receptor agonist AVE0991 was administered intranasally (0.9 mg/kg) after ICH. Using a combination of behavioral tests, Western blots, immunofluorescence staining, hematoma volume, brain edema, quantitative-PCR, TUNEL staining, Fluoro-Jade C staining, Nissl staining, and pharmacological methods, we examined the impact of intranasal application of AVE0991 on hematoma absorption and neurological outcomes following ICH and investigated the underlying mechanism. RESULTS: Mas receptor was found to be significantly expressed in activated microglia/macrophages, and the peak expression of Mas receptor in microglia/macrophages was observed at approximately 3-5 days, followed by a subsequent decline. Activation of Mas by AVE0991 post-treatment promoted hematoma absorption, reduced brain edema, and improved both short- and long-term neurological functions in ICH mice. Moreover, AVE0991 treatment effectively attenuated neuronal apoptosis, inhibited neutrophil infiltration, and reduced the release of inflammatory cytokines in perihematomal areas after ICH. Mechanistically, AVE0991 post-treatment significantly promoted the transformation of microglia/macrophages towards an anti-inflammatory, phagocytic, and reparative phenotype, and this functional phenotypic transition of microglia/macrophages by Mas activation was abolished by both Mas inhibitor A779 and Nrf2 inhibitor ML385. Furthermore, hematoma clearance and neuroprotective effects of AVE0991 treatment were reversed after microglia depletion in ICH. CONCLUSIONS: Mas activation can promote hematoma absorption, ameliorate neurological deficits, alleviate neuron apoptosis, reduced neuroinflammation, and regulate the function and phenotype of microglia/macrophages via Akt/Nrf2 signaling pathway after ICH. Thus, intranasal application of Mas agonist ACE0991 may provide promising strategy for clinical treatment of ICH patients.

Clearance of Neutrophils From ICH-Affected Brain by Macrophages Is Beneficial and Is Assisted by Lactoferrin and CD91.

BACKGROUND: Within hours after intracerebral hemorrhage (ICH) onset, masses of polymorphonuclear neutrophils (PMNs) infiltrate the ICH-affected brain. After degranulation involving controlled release of many toxic antimicrobial molecules, the PMNs undergo rapid apoptosis and then are removed by phagocytic microglia/macrophages (MΦ) through a process called efferocytosis. Effective removal of PMNs may limit secondary brain damage and inflammation; however, the molecular mechanisms governing these cleanup activities are not well understood. We propose that scavenger receptor CD91 on myeloid phagocytes especially in presence of CD91 ligand, LTF (lactoferrin, protein abundant in PMNs), plays an important role in clearance of dead apoptotic PMNs (ANs). METHODS: Mice/rats were subjected to an autologous blood injection model of ICH. Primary cultured microglia were used to assess phagocytosis of ANs. Immunohistochemistry was employed to assess CD91 expression and PMN infiltration. CD91 knockout mice selectively in myeloid phagocytes (Mac-CD91-KO) were used to establish the CD91/LTF function in phagocytosis and in reducing ICH-induced injury, as assessed using behavioral tests, hematoma resolution, and oxidative stress. RESULTS: Masses of PMNs are found in ICH-affected brain, and they contain LTF. MΦ at the outer border of hematoma are densely packed, expressing CD91 and phagocytosing ANs. Microglia deficient in CD91 demonstrate defective phagocytosis of ANs, and mice deficient in CD91 (Mac-CD91-KO) subjected to ICH injury have increased neurological dysfunction that is associated with impaired hematoma resolution (hemoglobin and iron clearance) and elevated oxidative stress. LTF that normally ameliorates ICH injury in CD91-proficient control mice shows reduced therapeutic effects in Mac-CD91-KO mice. CONCLUSIONS: Our study suggests that CD91 plays a beneficial role in improving ANs phagocytosis and ultimately post-ICH outcome and that the beneficial effect of LTF in ICH is in part dependent on presence of CD91 on MΦ.

Cigarette Smoking as a Risk Factor for Hematoma Expansion in Primary Intracerebral Hemorrhage: Analysis From a Randomized Clinical Trial.

Background Cigarette smoking is a well-known risk factor for ischemic and hemorrhagic stroke. We evaluated the impact of smoking status on hematoma expansion and clinical outcome in patients with primary intracerebral hemorrhage. Methods and Results This is a post hoc exploratory analysis of the ATACH (Antihypertensive Treatment at Acute Cerebral Hemorrhage)-2 trial. Patients with intracerebral hemorrhage were randomized into intensive blood pressure lowering (systolic blood pressure, <139 mm Hg) versus standard blood pressure lowering (systolic blood pressure, 140-179 mm Hg) in this study. We compared the demographic characteristics; hematoma size, location, and expansion rate; and clinical outcome based on subjects' smoking status. Of a total of 914 patients in the trial with known smoking status, 439 (48%) patients were ever smokers (264 current smokers and 175 former smokers). Current and former smokers were younger and more likely to be men. Baseline Glasgow Coma Scale score and initial hematoma size did not vary based on smoking status. Ever smokers had higher rates of thalamic hemorrhage (42% versus 34%) and intraventricular hemorrhage (29% versus 23%); this rate was highest among former smokers versus current smokers (49% versus 35%, respectively). Ever smokers had a higher rate of hematoma expansion in 24 hours (adjusted relative risk [RR] [95% CI], 1.46 [1.08-1.96]) compared with nonsmokers on multivariate analysis. There was no significant difference in the rate of death and disability at 90 days between the 2 groups (adjusted RR [95% CI], 1.18 [0.998-1.40]). Conclusions Our analysis demonstrates cigarette smoking as an independent predictor for hematoma expansion. There was no significant difference in death and disability based on smoking status.

[Pulmonary embolism in neurosurgical patients]. / Tromboemboliya legochnoi arterii u patsientov neirokhirurgicheskogo profilya.

Pulmonary embolism (PE) is a serious problem for neurosurgical patients because of high risk of mortality and the need to choose effective and safe anticoagulation. OBJECTIVE: To analyze the patients with PE after neurosurgical interventions. MATERIAL AND METHODS: A prospective study was performed at the Burdenko Neurosurgical Center between January 2021 and December 2022. Inclusion criteria were neurosurgical disease and PE. RESULTS: In accordance with inclusion criteria, we analyzed 14 patients. Mean age was 63 [45.8; 70.0] years. Four patients died. PE was a direct cause of death in 1 case. PE occurred in 5.14±3.68 days after surgery. Anticoagulation was safely implemented in 3 patients with PE on the first day after craniotomy. In a patient with massive PE several hours after craniotomy, anticoagulation resulted hematoma with brain dislocation and death. Thromboextraction and thrombodestruction were used in 2 patients with massive PE and high risk of mortality. CONCLUSION: Despite low incidence (0.1%), PE is a serious problem in neurosurgical patients due to the risk of intracranial hematoma under effective anticoagulant therapy. In our opinion, endovascular interventions with thromboextraction, thrombodestruction or local fibrinolysis are the safest in the treatment of PE after neurosurgery. Individual approach considering clinical, laboratory data, advantages and disadvantages of a particular anticoagulant drug is required when choosing the tactics of anticoagulation. Further analysis of a larger number of clinical cases is needed to develop the guidelines for the management of neurosurgical patients with PE.

The Development of Drug Delivery Systems for Efficient Intracranial Hemorrhage Therapy.

Intracerebral hemorrhage (ICH) is the most devastating form of stroke, which accounts for 10-15% of cases and causes high morbidity and mortality. With the continuous exploration of the pathological mechanism of ICH, extensive research focusing on ICH therapy has been conducted. However, the traditional treatment methods, such as surgery for removing the hematoma and pharmacotherapy for improving the clearance of the hematoma and neuroprotection, are greatly limited due to their poor practicality and treatment efficiency. The rapid development of drug delivery systems offers an important prospect for treating ICH as they exhibit great versatility, which can improve the pharmacokinetic behavior of drugs in vivo, increase the drug accumulation in specific cell types or tissues, and enhance the therapeutic effect with diminished toxic effect. In this review, the main molecular pathological mechanisms of ICH are comprehensively described and the limitation of traditional pharmacotherapy are also discussed. Then the development based on drug delivery systems for treating ICH is highlighted. Finally, based on these discussions the challenges of drug delivery systems with a view to providing a new feasible path for the treatment of ICH are summarized.

Magnetic Targeting Nanocarriers Combined with Focusing Ultrasound for Enhanced Intracerebral Hemorrhage Therapy.

Intracerebral hemorrhage (ICH) remains a significant cause of morbidity and mortality around the world, and surgery is still the most direct and effective way to remove ICH. However, the potential risks brought by surgery, such as normal brain tissue damage, post-operative infection, and difficulty in removing deep hematoma, are still the main problems in the surgical treatment of ICH. Activation of the peroxisome proliferator-activated receptor gamma (PPARγ) is reported to show a good therapeutic effect in hematoma clearance. Herein, a magnetic targeting nanocarrier loaded with a PPARγ agonist (15d-PGJ2-MNPs) is synthesized, which could be magnetically targeted and enriched in the area of the hematoma after intravenous injection. Subsequent application of focusing ultrasound (FUS) could enhance drug diffusion, which activates the PPARγ receptors on macrophages around the hematoma for better hematoma clearance. The 15d-PGJ2-MNP treatment alleviates brain injury, accelerates hematoma clearance, attenuates neuroinflammation, reduces brain edema and significantly improves the deficits in sensory and motor function and spatial learning ability in the ICH mouse model. This work proposes an effective magnetic targeting plus FUS method to treat ICH, highlighting its great potential in the treatment of hemorrhagic stroke.

Intravenous Tranexamic Acid in Percutaneous Kidney Biopsy: A Randomized Controlled Trial.

BACKGROUND: Tranexamic acid is frequently reported to reduce bleeding-related complications in major surgery and trauma. We aimed to investigate whether tranexamic acid reduced hematoma size after percutaneous kidney biopsy. METHODS: We conducted a double-blind, parallel three-group, randomized placebo-controlled trial at a teaching hospital in Japan between January 2016 and July 2018. Adult patients with clinical indication for ultrasound-guided percutaneous biopsy of a native kidney were included. Participants were randomly assigned into three groups: high-dose tranexamic acid (1,000 mg in total), low-dose tranexamic acid (500 mg in total), or placebo (counterpart saline). Intervention drugs were intravenously administered twice, as a bolus just before the biopsy and as a continuous infusion initiated just after the biopsy. Primary outcome was post-biopsy perirenal hematoma size as measured by ultrasound on the morning after the biopsy. RESULTS: We assessed 90 adult patients for study eligibility, of whom 56 were randomly allocated into the three groups: 20 for high-dose tranexamic acid, 19 for low-dose tranexamic acid, and 17 for placebo. The median size of perirenal hematoma was 200 mm2 (interquartile range, 21-650) in the high-dose tranexamic acid group, 52 mm2 (0-139) in the low-dose tranexamic acid group, and 0 mm2 (0-339) in the placebo group (p = 0.048 for high-dose tranexamic acid vs. placebo). CONCLUSION: In this trial, the median size of post-kidney biopsy hematoma was unexpectedly larger in the high-dose tranexamic acid group than in the placebo group. Although our results do not support the routine use of tranexamic acid in percutaneous kidney biopsy at present, further studies are needed to confirm the results.

Comparison between rivaroxaban versus enoxaparin for venous thromboembolism prophylaxis following spine surgeries, a randomized clinical trial.

BACKGROUND: Enoxaparin is currently used for VTE prophylaxis. Rivaroxaban is more cost-effective and is as potent as enoxaparin in VTE prophylaxis. METHODS: The study was held at Al-Zahra and Kashani university hospitals in Isfahan, Iran, from January 2019 to October 2020. Two hundred ninety-six patients requiring instrumented spine surgery were enrolled; 23 were excluded (lack of consent/interfering medical situations). They were randomized into the groups of rivaroxaban (case, n = 137) and enoxaparin receiving (control, n = 136). Medical data were recorded and 244 patients (case = 123, control = 121) were analyzed value < 0.05 was meaningful. RESULTS: 150 patients were males, and 94 were females. The mean age was 52.09 ± 12.6 years. Postoperative drain volume was higher in rivaroxaban received patients than in enoxaparin (p = 0.02). Post-operation epidural hematoma was detected in 3 patients in the case and 1 in the control group, which was not meaningful(p = 0.622). All of them were evacuated surgically. POH was associated with cervical canal stenosis surgery, existing comorbidities, and new medical events. New medical events were associated with postoperative wound dehiscence (p = 0.001). Short and long-term postoperative outcomes were similar in both groups. The mean follow-up duration was 25.8 ± 7.5 months. CONCLUSION: Rivaroxaban is as effective as enoxaparin in venous thromboembolic event prophylaxis. Regarding postoperative epidural hematoma, statistical analysis showed equal safety of both drugs. Still, the authors would like to recommend more discretion in rivaroxaban administration in cervical spine laminectomy until future studies are conducted.

Desmopressin Acetate in Percutaneous Ultrasound-Guided Native Kidney Biopsy in Patients with Reduced Kidney Function: A Double-Blind Randomized Controlled Trial.

INTRODUCTION: Bleeding events are the most common complications after kidney biopsy. This study aims to evaluate the effect of desmopressin administration on bleeding complication, in native kidney biopsy candidates with reduced kidney function. METHODS: This double-blind randomized clinical trial enrolled 18 to 80 years old patients with 15 < eGFR < 90 mL/min/ 1.73m² from July 2017 to August 2020. Patients were randomly assigned to receive either 3 µg/kg of intranasal desmopressin acetate or 1 mL/kg of intranasal sodium chloride 0.65%, one hour before ultrasound-guided, percutaneous native kidney biopsy. The primary outcome was the post-biopsy bleeding complications, and secondary outcomes were the volume of perirenal hematoma, and changes of post-biopsy hemoglobin and hematocrit level, plasma sodium and blood pressure (Clinical Trial Registration ID: IRCT20090701002112N3). RESULTS: A total of 120 patients (58 men and 62 women), 60 patients in each group, were analyzed. The mean age and eGFR of the patients were 45.29 ± 15.95 years and 51.77 ± 18.02 ml/min/ 1.73m², respectively. Desmopressin administration significantly decreased post-biopsy perirenal hematoma compared to placebo (7/60 [11.6%]) vs. 33/60 [40%]; P < .05), and the hematoma volume was significantly smaller in the desmopressin group, in case of hematoma formation (2.31 ± 1.17 vs. 7.72 ± 5.45 mm³, P < .05). CONCLUSION: Desmopressin administration before kidney biopsy is a safe and effective strategy to prevent bleeding complications. Considering absolute risk reduction of about 28%, the number needed to treat is about 4 procedures. We recommend considering desmopressin administration before percutaneous native kidney biopsy.  DOI: 10.52547/ijkd.6966.

Distinct Behavior of Traumatic versus Nontraumatic Intracerebral Hematomas: Different Biology or Impact of Age?

BACKGROUND AND STUDY AIMS: Patients with large intracerebral hematomas (ICH) may demonstrate different demographics and underlying brain and systemic diseases, as well as different radiologic courses and distinct outcomes. It remains unclear whether their different behavior attributes to a different biology of the ICH or to the asymmetric characteristics of the two populations. To analyze and adjust for potential sources of selection and treatment bias, our study compared age-matched patients with traumatic and nontraumatic ICH in a single cohort diagnosed and treated in the same surgical department. MATERIAL AND METHODS: We analyzed 135 consecutive patients with traumatic (n = 90) or spontaneous ICH (n = 45) undergoing treatment at a surgical intensive care unit of an urban university hospital. We documented their differences before and after adjustment for age in terms of demographics, the therapies applied, their radiologic (i.e., volume and rate of ICH expansion [HE]) and clinical (patients' outcome at 30 days) course, the length of hospital and ICU stay, as well as the hospital costs. RESULTS: Patients with traumatic ICH demonstrated more favorable clinical and radiologic characteristics at admission, that is, higher Glasgow Coma Scale score (p < 0.001), less frequently dilated pupil (p = 0.028), lower Charlson Comorbidity Index (p < 0.001), smaller ICH volume (p < 0.001), noneloquent (p < 0.001) or nonintraventricular (p = 0.003) ICH locations, as well as underwent fewer neurosurgical interventions (p < 0.001) and showed a better outcome (p = 0.041), defined as Glasgow Outcome Scale 4 and 5. After adjustment for age, no different outcomes were observed. Of note, elderly patients on novel oral anticoagulants (NOACs) were more likely to develop an HE compared with those on vitamin K antagonists (VKAs, p = 0.05) after traumatic brain injury (TBI) but not after spontaneous ICH. CONCLUSION: Our data reveal a significant heterogeneity within the traumatic series. Whereas younger patients show an excellent outcome, the elderly population of the traumatic cases demonstrates a poor outcome similar to that of the nontraumatic cohort. HE under NOACs rather than under VKAs is more likely in the elderly after TBI. Larger prospective trials are warranted to elucidate the potential individual underlying molecular mechanisms for the development of an ICH and HE in these diseases.

Pharmacological Activation of RXR-α Promotes Hematoma Absorption via a PPAR-γ-dependent Pathway After Intracerebral Hemorrhage.

Endogenously eliminating the hematoma is a favorable strategy in addressing intracerebral hemorrhage (ICH). This study sought to determine the role of retinoid X receptor-α (RXR-α) in the context of hematoma absorption after ICH. Our results showed that pharmacologically activating RXR-α with bexarotene significantly accelerated hematoma clearance and alleviated neurological dysfunction after ICH. RXR-α was expressed in microglia/macrophages, neurons, and astrocytes. Mechanistically, bexarotene promoted the nuclear translocation of RXR-α and PPAR-γ, as well as reducing neuroinflammation by modulating microglia/macrophage reprograming from the M1 into the M2 phenotype. Furthermore, all the beneficial effects of RXR-α in ICH were reversed by the PPAR-γ inhibitor GW9662. In conclusion, the pharmacological activation of RXR-α confers robust neuroprotection against ICH by accelerating hematoma clearance and repolarizing microglia/macrophages towards the M2 phenotype through PPAR-γ-related mechanisms. Our data support the notion that RXR-α might be a promising therapeutic target for ICH.

IL-4/STAT6 signaling facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice.

Intracerebral hemorrhage (ICH) is a devastating form of stroke affecting millions of people worldwide. Parenchymal hematoma triggers a series of reactions leading to primary and secondary brain injuries and permanent neurological deficits. Microglia and macrophages carry out hematoma clearance, thereby facilitating functional recovery after ICH. Here, we elucidate a pivotal role for the interleukin (IL)-4)/signal transducer and activator of transcription 6 (STAT6) axis in promoting long-term recovery in both blood- and collagenase-injection mouse models of ICH, through modulation of microglia/macrophage functions. In both ICH models, STAT6 was activated in microglia/macrophages (i.e., enhanced expression of phospho-STAT6 in Iba1+ cells). Intranasal delivery of IL-4 nanoparticles after ICH hastened STAT6 activation and facilitated hematoma resolution. IL-4 treatment improved long-term functional recovery in young and aged male and young female mice. In contrast, STAT6 knockout (KO) mice exhibited worse outcomes than WT mice in both ICH models and were less responsive to IL-4 treatment. The construction of bone marrow chimera mice demonstrated that STAT6 KO in either the CNS or periphery exacerbated ICH outcomes. STAT6 KO impaired the capacity of phagocytes to engulf red blood cells in the ICH brain and in primary cultures. Transcriptional analyses identified lower level of IL-1 receptor-like 1 (ST2) expression in microglia/macrophages of STAT6 KO mice after ICH. ST2 KO diminished the beneficial effects of IL-4 after ICH. Collectively, these data confirm the importance of IL-4/STAT6/ST2 signaling in hematoma resolution and functional recovery after ICH. Intranasal IL-4 treatment warrants further investigation as a clinically feasible therapy for ICH.

Minimally invasive surgery for haemophilic pseudotumour of the limbs: 28 years of experience.

INTRODUCTION: Haemophilic pseudotumour (HP) is an encapsulated haematoma in patients with haemophilia (PWH) which has a tendency to progress and produce clinical symptoms related to its anatomical location. AIM: To show the experience of one surgeon who has been using mini-invasive technique to treat pseudotumours of limbs in PWH with and without inhibitors at one centre for 28 years. MATERIALS AND METHODS: Thirty-three patients with 39 HP were treated. All patients had haemophilia A. Twenty-four patients had no inhibitors (72.8%), and 9 had inhibitors (27.2%). The mean follow-up was 16 years (1-25). All patients had x-rays and MRIs. All of them received Buenos Aires protocol as conservative treatment for 6 weeks. MRIs were repeated after 6 weeks' treatment to assess response to treatment. Surgery was performed in patients who did not respond to conservative treatment. RESULTS: After Buenos Aires protocol, four pseudotumours did not shrink (10.24%), 33 (84.61%) shrank, and two (5.12%) healed. Thirty-seven pseudotumours had surgery, 35 pseudotumours (94.59%) healed with minimally invasive treatment, and two did not heal (5.41%). No infection was observed with this treatment. The mortality rate for the series was 0%. CONCLUSION: The minimally invasive treatment of pseudotumours was effective in 95% of the cases and resulted in no mortality in this series after 28 years.

Successful treatment of hemorrhagic brainstem cavernous malformation with hematoma evacuation and postoperative propranolol.

In this case, we describe an evident hemorrhagic brainstem cavernous malformation successfully treated with a planned sequence of surgical evacuation of the hematoma followed by postoperative propranolol therapy. In contrast to common practice, the cavernoma itself was not resected. A nearly 3-year-old male presented with altered mental status, gait disturbance, and facial palsy. CT and MRI demonstrated a large acute pontine hematoma. A large nearby vein suggested cavernous malformation. He was initially treated conservatively but a repeat CT scan demonstrated further expansion of hematoma and he was taken emergently to the OR. Due to the sensitive location of the hematoma in the pons, we planned to evacuate the hematoma without resecting any of the presumed cavernoma. Instead, we planned to treat the cavernoma with propranolol. Postoperatively, the patient's condition improved and was still improving at hospital discharge 2 weeks later. Six-month follow-up MRI showed no cavernoma with only hemosiderin at the site of the evacuated hematoma. This is the first reported case of a hemorrhagic brainstem cavernous malformation treated with a planned sequence of hematoma evacuation followed by propranolol without an attempt to resect the cavernoma.

[Treatment of submacular hematoma by vitrectomy, subretinal injection of rtPA and gaseous tamponade: A single-center retrospective observational study]. / Traitement des hématomes sous-maculaires par vitrectomie, injection sous-rétinienne de rtPA et tamponnement gazeux : une étude observationnelle rétrospective monocentrique.

OBJECTIVES: To evaluate the functional and anatomic recovery of submacular hemorrhage (SMH), treated with vitrectomy, subretinal injection of rtPA and gas tamponade, to highlight the risk factors for their occurrence as well as the factors influencing prognosis. MATERIALS AND METHODS: This is a single-center retrospective study. Thirty-two eyes of 30 patients from the Clermont-Ferrand University Hospital were included, with a submacular hemorrhage (SMH) requiring surgical evacuation. The primary endpoint was final postoperative visual recovery. Visual acuities (AV) were converted to the logarithmic minimum angle of resolution scale (logMAR) for statistical analysis. RESULTS: The average time from onset of symptoms to surgery was 4.8±3.3 days. The initial VA was 2.1±0.3 logMAR, with an average improvement of 0.7±0.7 logMAR (P=0.0004) at the final visit. The mean thickness of the SMH decreased by 729±352µm (P<0.0001) at the final visit. CONCLUSION: Treatment of SMH with vitrectomy, subretinal injection of rtPA and gas tamponade results in a statistically significant improvement in final VA, as well as a significant decrease in SMH thickness on OCT.

Bexarotene Enhances Macrophage Erythrophagocytosis and Hematoma Clearance in Experimental Intracerebral Hemorrhage.

Background and Purpose- Enhancement of erythrophagocytosis by macrophages in a timely manner can limit the toxic effects of erythrocyte metabolites and promote brain recovery after intracerebral hemorrhage (ICH). In the current study, we investigated the therapeutic effect of retinoid X receptor agonist, bexarotene, in facilitating erythrophagocytosis and neurobehavioral recovery in 2 mouse models of ICH. Methods- Bone marrow-derived macrophages and fluorescently labeled erythrocytes were used to study erythrophagocytosis in vitro with phenotypic changes quantified by gene expression. ICH was modeled in vivo using intrastriatal autologous blood and collagenase injection in mice with and without bexarotene treatment beginning 3 hours after ICH. In vivo phagocytosis, ability and hematoma clearance were evaluated by erythrophagocytosis assays, flow cytometry, and histological analysis. Neurological deficits and functional recovery were also quantified. Results- Bexarotene increased macrophage expression of phagocytosis receptors and erythrophagocytosis and reduced macrophage TNF (tumor necrosis factor) production in vitro. In vivo, bexarotene treatment enhanced erythrophagocytosis, reduced hematoma volume, and ultimately improved neurological recovery after ICH in 2 distinct models of ICH. Conclusions- Bexarotene administration is beneficial for recovery after ICH by enhancing hemorrhage phagocytosis, modulating macrophage phenotype, and improving functional recovery.

End-of-Treatment Intracerebral and Ventricular Hemorrhage Volume Predicts Outcome: A Secondary Analysis of MISTIE III.

Background and Purpose- Trials have shown potential clinical benefit for minimally invasive clot evacuation of intracerebral hemorrhage (ICH). Prior research showing an association between ICH size and functional outcome did not fully address the spectrum of hematoma volumes seen after clot evacuation. Methods- In this secondary analysis of the MISTIE III trial (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation III), we included patients randomized to the surgical arm. The primary outcome was good outcome (modified Rankin Scale score 0-3 at 1 year from study enrollment). The primary predictors were the end-of-treatment (EoT) ICH and intraventricular hemorrhage volumes and an end-of-treatment ICH stratification scale called the EoT ICH volume score. Results- In 246 patients, the end-of-treatment computed tomography was performed an average of 5 days from onset. For patients with good versus poor outcomes, the mean end-of-treatment ICH and intraventricular hemorrhage volumes were 12.9 versus 18.0 mL (P=0.002) and 0.5 versus 2.3 mL (P<0.001), respectively. The probability of a good outcome decreased from 73% for EoT ICH volume 3 (<5 mL) to 28% for EoT ICH volume 0 (>20 mL; P=0.001). Conclusions- After surgical clot evacuation, both ICH and intraventricular hemorrhage volumes have a strong association with good neurological outcome. The EoT ICH volume score needs independent verification, but such an approach could be used for prognostication and therapeutic planning.