BACKGROUND
There is much uncertainty about the effects of early lowering of elevated blood pressure (BP) after acute intracerebral haemorrhage (ICH). Our aim was to assess the safety and efficiency of this treatment, as a run-in phase to a larger trial.


METHODS
Patients who had acute spontaneous ICH diagnosed by CT within 6 h of onset, elevated systolic BP (150-220 mm Hg), and no definite indication or contraindication to treatment were randomly assigned to early intensive lowering of BP (target systolic BP 140 mm Hg; n=203) or standard guideline-based management of BP (target systolic BP 180 mm Hg; n=201). The primary efficacy endpoint was proportional change in haematoma volume at 24 h; secondary efficacy outcomes included other measurements of haematoma volume. Safety and clinical outcomes were assessed for up to 90 days. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00226096.


FINDINGS
Baseline characteristics of patients were similar between groups, but mean haematoma volumes were smaller in the guideline group (12.7 mL, SD 11.6) than in the intensive group (14.2 mL, SD 14.5). From randomisation to 1 h, mean systolic BP was 153 mm Hg in the intensive group and 167 mm Hg in the guideline group (difference 13.3 mm Hg, 95% CI 8.9-17.6 mm Hg; p<0.0001); from 1 h to 24 h, BP was 146 mm Hg in the intensive group and 157 mm Hg in the guideline group (10.8 mm Hg, 95% CI 7.7-13.9 mm Hg; p<0.0001). Mean proportional haematoma growth was 36.3% in the guideline group and 13.7% in the intensive group (difference 22.6%, 95% CI 0.6-44.5%; p=0.04) at 24 h. After adjustment for initial haematoma volume and time from onset to CT, median haematoma growth differed between the groups with p=0.06; the absolute difference in volume between groups was 1.7 mL (95% CI -0.5 to 3.9, p=0.13). Relative risk of haematoma growth >or=33% or >or=12.5 mL was 36% lower (95% CI 0-59%, p=0.05) in the intensive group than in the guideline group. The absolute risk reduction was 8% (95% CI -1.0 to 17%, p=0.05). Intensive BP-lowering treatment did not alter the risks of adverse events or secondary clinical outcomes at 90 days.


INTERPRETATION
Early intensive BP-lowering treatment is clinically feasible, well tolerated, and seems to reduce haematoma growth in ICH. A large randomised trial is needed to define the effects on clinical outcomes across a broad range of patients with ICH.


FUNDING
National Health and Medical Research Council of Australia.

Intensive blood pressure reduction in acute cerebralhaemorrhage trial (INTERACT): a randomised pilot trial

わが国における成人市中肺炎の原因微生物の変遷(Meta‐analysis and systematic review)

Idarucizumab for dabigatran reversal

The blood-brain barrier (BBB) is a critical regulator of CNS homeostasis. It possesses physical and biochemical characteristics (i.e. tight junction protein complexes, transporters) that are necessary for the BBB to perform this physiological role. Microvascular endothelial cells require support from astrocytes, pericytes, microglia, neurons, and constituents of the extracellular matrix. This intricate relationship implies the existence of a neurovascular unit (NVU). NVU cellular components can be activated in disease and contribute to dynamic remodeling of the BBB. This is especially true of microglia, the resident immune cells of the brain, which polarize into distinct proinflammatory (M1) or anti-inflammatory (M2) phenotypes. Current data indicate that M1 pro-inflammatory microglia contribute to BBB dysfunction and vascular "leak", while M2 anti-inflammatory microglia play a protective role at the BBB. Understanding biological mechanisms involved in microglia activation provides a unique opportunity to develop novel treatment approaches for neurological diseases. In this review, we highlight characteristics of M1 proinflammatory and M2 anti-inflammatory microglia and describe how these distinct phenotypes modulate BBB physiology. Additionally, we outline the role of other NVU cell types in regulating microglial activation and highlight how microglia can be targeted for treatment of disease with a focus on ischemic stroke and Alzheimer's disease.

Regulation of blood-brain barrier integrity by microglia in health and disease: A therapeutic opportunity.

Ischemic stroke is one of the leading causes of mortality and disability worldwide. However, there is a current lack of effective therapies available. As the resident macrophages of the brain, microglia can monitor the microenvironment and initiate immune responses. In response to various brain injuries, such as ischemic stroke, microglia are activated and polarized into the proinflammatory M1 phenotype or the anti‑inflammatory M2 phenotype. The immunomodulatory molecules, such as cytokines and chemokines, generated by these microglia are closely associated with secondary brain damage or repair, respectively, following ischemic stroke. It has been shown that M1 microglia promote secondary brain damage, whilst M2 microglia facilitate recovery following stroke. In addition, autophagy is also reportedly involved in the pathology of ischemic stroke through regulating the activation and function of microglia. Therefore, this review aimed to provide a comprehensive overview of microglia activation, their functions and changes, and the modulators of these processes, including transcription factors, membrane receptors, ion channel proteins and genes, in ischemic stroke. The effects of autophagy on microglia polarization in ischemic stroke were also reviewed. Finally, future research areas of ischemic stroke and the implications of the current knowledge for the development of novel therapeutics for ischemic stroke were identified.

/pdf/modulators-of-microglia-activation-and-polarization-in-3w3pobi7hr.pdf

Modulators of microglia activation and polarization in ischemic stroke (Review).

Endothelium (EC) is a key component of blood–brain barrier (BBB), and has an important position in the neurovascular unit. Its dysfunction and death after cerebral ischemic/reperfusion (I/R) injury not only promote evolution of neuroinflammation and brain edema, but also increase the risk of intracerebral hemorrhage of thrombolytic therapies. However, the mechanism and specific interventions of EC death after I/R injury are poorly understood. Here we showed that necroptosis was a mechanism underlying EC death, which promoted BBB breakdown after I/R injury. Treatment of rats with receptor interacting protein kinase 1 (RIPK1)-inhibitor, necrostatin-1 reduced endothelial necroptosis and BBB leakage. We furthermore showed that perivascular M1-like microglia-induced endothelial necroptosis leading to BBB disruption requires tumor necrosis factor-α (TNF-α) secreted by M1 type microglia and its receptor, TNF receptor 1 (TNFR1), on endothelium as the primary mediators of these effects. More importantly, anti-TNFα (infliximab, a potent clinically used drug) treatment significantly ameliorate endothelial necroptosis, BBB destruction and improve stroke outcomes. Our data identify a previously unexplored role for endothelial necroptosis in BBB disruption and suggest infliximab might serve as a potential drug for stroke therapy.

/pdf/microglia-derived-tnf-a-mediates-endothelial-necroptosis-2dho91g1fn.pdf

Microglia-derived TNF-α mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke.

Intracerebral hemorrhage (ICH) is the most lethal type of stroke, but there is no specific treatment. After years of effort, neurologists have found that hematoma expansion (HE) is a vital predictor of poor prognosis in ICH patients, with a not uncommon incidence ranging widely from 13 to 38%. Herein, the progress of studies on HE after ICH in recent years is updated, and the topics of definition, prevalence, risk factors, prediction score models, mechanisms, treatment, and prospects of HE are covered in this review. The risk factors and prediction score models, including clinical, imaging, and laboratory characteristics, are elaborated in detail, but limited by sensitivity, specificity, and inconvenience to clinical practice. The management of HE is also discussed from bench work to bed practice. However, the upmost problem at present is that there is no treatment for HE proven to definitely improve clinical outcomes. Further studies are needed to identify more accurate predictors and effective treatment to reduce HE.

/pdf/hematoma-expansion-in-intracerebral-hemorrhage-an-update-on-5a5kp126j5.pdf

Hematoma Expansion in Intracerebral Hemorrhage: An Update on Prediction and Treatment

Neuron derived fractalkine promotes microglia to absorb hematoma via CD163/HO-1 after intracerebral hemorrhage

Intracerebral hemorrhage (ICH) features extremely high rates of morbidity and mortality, with no specific and effective therapy. And local inflammation caused by the over-activated immune cells seriously damages the recovery of neurological function after ICH. Fortunately, immune intervention to microglia has provided new methods and ideas for ICH treatment. Microglia, as the resident immune cells in the brain, play vital roles in both tissue damage and repair processes after ICH. The perihematomal activated microglia not only arouse acute inflammatory responses, oxidative stress, excitotoxicity, and cytotoxicity to cause neuron death, but also show another phenotype that inhibit inflammation, clear hematoma and promote tissue regeneration. The proportion of microglia phenotypes determines the progression of brain tissue damage or repair after ICH. Therefore, microglia may be a promising and imperative therapeutic target for ICH. In this review, we discuss the dual functions of microglia in the brain after an ICH from immunological perspective, elaborate on the activation mechanism of perihematomal microglia, and summarize related therapeutic drugs researches.

/pdf/microglia-phenotype-and-intracerebral-hemorrhage-a-balance-2pa4zqq0uc.pdf

Microglia Phenotype and Intracerebral Hemorrhage: A Balance of Yin and Yang.

Spontaneous intracerebral hemorrhage (ICH) is a common fatal event without an effective therapy. Of note, some familial aggregation and inherited tendency is found in ICH and heritability estimates indicate that genetic variations contribute substantially to ICH risk and outcome. Thus, identification of genetic variants that affect the occurrence and outcome may be helpful for ICH prevention and therapy. There are several reviews summarizing numerous genetic variants associated with the occurrence of ICH before, but genetic variants contributing to location distribution and outcome have rarely been introduced. Here, we summarize the current knowledge of genetic variants and pay special attention to location distribution and outcome. So far, investigations have reveled variations in APOE, GPX1, CR1, ITGAV, PRKCH, and 12q21.1 are associated with lobar ICH (LICH), while ACE, COL4A2, 1q22, TIMP1, TIMP2, MMP2, MMP9, and TNF are associated with deep ICH (DICH). Moreover, variations in APOE, VWF, 17p12, HP, CFH, IL6ST, and COL4A1 are possible genetic contributors to ICH outcome. Furthermore, the prospects for ICH related genetic studies from the bench to the bed were discussed. Graphical Abstract

/pdf/genetics-of-spontaneous-intracerebral-hemorrhage-risk-and-17ihb6df.pdf

Mingfeng You

Papers

Microglia-derived TNF-α mediates endothelial necroptosis aggravating blood brain-barrier disruption after ischemic stroke.

Hematoma Expansion in Intracerebral Hemorrhage: An Update on Prediction and Treatment

Neuron derived fractalkine promotes microglia to absorb hematoma via CD163/HO-1 after intracerebral hemorrhage

Microglia Phenotype and Intracerebral Hemorrhage: A Balance of Yin and Yang.

Genetics of Spontaneous Intracerebral Hemorrhage: Risk and Outcome