A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors

Protein arginine methyltransferases (PRMTs) are attractive targets for developing therapeutic agents, but selective PRMT inhibitors targeting the cofactor SAM binding site are limited. Herein, we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guanidine of a pan-PRMT inhibitor with a benzyl urea, potently and selectively inhibiting PRMT3/4/5. Importantly, crystal structures reveal that the benzyl urea moiety of YD1113 induces a unique and novel hydrophobic binding pocket in PRMT3/4, providing a structural basis for the selectivity. In addition, YD1113 can be modified by introducing a substrate mimic to form a "T-shaped" bisubstrate analogue YD1290 to engage both the SAM and substrate binding pockets, exhibiting potent and selective inhibition to type I PRMTs (IC50 < 5 nmol/L). In summary, we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors.

Role of External Ventricular Drainage (EVD) in Treating Spontaneous Intraventricular Haemorrhage

Background: There is no consensus in the literature on the effects of the development of hydrocephalus on survival and disability after intracerebral haemorrhage (ICH) and the benefits of external ventricular drainage (EVD). This study is planned to describe the role of external ventricular drainage in treating patients of spontaneous, either primary or secondary, intraventricular haemorrhage with hydrocephalus.Material & Methods:A hospital based prospective interventional study was conducted in the Department of Neurosurgery of Dhaka Medical College Hospital, which is a tertiary level hospital, from April 2016 to September 2017.Total 42 patients of spontaneous intraventricular haemorrhage, either primary or secondary, with hydrocephalus were selected for this study. All the collected data were entered into IBM SPSS software, Version 24. For statistical analysis, paired t-test to compare the preoperative GCS with postoperative GCS at 24 hours was done.Results:Among 42 patients, age range was 26-75 years with the mean age 65.2 � 10.87 years. Male were 26 (61.9%) and female were 16 (38.1%). Male-Female ratio was 1.625:1. No patient needed conversion of EVD into VP shunt. EVD drain became blocked in 5 cases which were managed accordingly. 5 patients developed ventriculitis among which 2 patients died and rest 3 improved with antibiotics.Conclusions:The results of present study shows that EVD has a good role in the treatment of spontaneous IVH with hydrocephalus when ICH volume is low (<30ml) and modified Graeb Score is low (?10 found in this in this study. Preoperative higher GCS or initial improvement in GCS or initial improvement in GCS at 24 hours positively correlates with Glasgow outcome scale which is an indication of good function outcome.

Subarachnoid haemorrhage mimicking unstable angina: a case report

Subarachnoid haemorrhage (SAH) is medical emergency caused by bleeding into the subarachnoid space. It is caused by rupture of an aneurysm or arteriovenous malformations (AVM). Symptoms of SAH are severe headache, nausea, vomiting, impaired consciousness and seizures. Neck stiffness and neck pain are relatively uncommon. Risk factors are high blood pressure, smoking, family history, alcoholism and even cocaine use. Diagnosis is mainly made by CT scan of head which should be done within six hours of the onset of symptoms and occasionally lumber puncture can also be done. An electrocardiogram (ECG) of all patients with subarachnoid should be done because patient with SAH can have myocardial ischemia due to increased level of circulating catecholamines or due to autonomic stimulation of the brain. ECG changes associated with SAH primarily reflect repolarisation abnormalities involving ST segment, T wave, U wave and QTc interval. Myocardial ischemia or infarction is often suspected in patients with SAH. Even troponin levels may be raised in these patients. However, suspicion of SAH is a contraindication for thrombolytic and anticoagulant therapy. This is a case of SAH which was initially treated for acute coronary syndrome (ACS) on the basis of symptoms and gradually changing ECG findings but on CT Head, patient was having SAH.

Preparation of a rat model of subarachnoid hemorrhage by a fiber core inserted in the internal carotid artery / 中国比较医学杂志

Objective To report a newly developed method and procedure to establish a rat model of subarachnoid hemorrhage in detail, and to provide a better model simulating the clinical subarachnoid hemorrhage caused by a ruptured aneurysm for related research.Methods One hundred and twenty healthy SPF 2-3-month old male Sprague-Dawley rats were divided into 4 groups, 30 rats in each group.The three experimental groups were sacrificed at 6, 24 and 72 hours after modeling.Rat models of subarachnoid hemorrhage were established by inserting a fiber core in the internal carotid artery and piercing this artery.Successful establishment of the subarachnoid hemorrhage model was confirmed by observation of breathing, pupil, defecation, urination and inspection at autopsy dissection.The controllability and reproducibility of this model were verified by observation of clinical manifestation and explored by mortality analysis.Results Subarachnoid hemorrhage was successfully induced by fiber core piercing the internal carotid artery at the needed location.Conclusions This method of model preparation is stable and understandable.The operation is nimble, with a good reproducibility.This model can be successfully performed after a short time learning, well simulate the sudden hemorrhage caused by a ruptured aneurysm, and suitable for research on early brain injury and vasospasm after subarachnoid hemorrhage.

Endovascular Treatment of a Fusiform Aneurysm Involving a Premammillary Artery Originating from the Internal Carotid Artery: A Case Report

The premammillary artery (PMA) is a branch of the posterior communicating artery (PCoA). While the PMA is known to originate from the PCoA as demonstrated by most anatomical studies, it originates directly from the internal carotid artery in approximately 1% of patients. Cerebral aneurysms associated with the PMA have rarely been reported. We report an extremely rare case of a ruptured PMA aneurysm that was managed using endovascular treatment.

Contrast Extravasation on Computed Tomography Angiography Imitating a Basilar Artery Trunk Aneurysm in Subsequent Conventional Angiogram-Negative Subarachnoid Hemorrhage: Report of Two Cases with Different Clinical Courses

Contrast extravasation on computed tomography angiography (CTA) is rare but becoming more common, with increasing use of CTA for various cerebral vascular diseases. We report on two cases of spontaneous subarachnoid hemorrhage (SAH) in which the CTA showed an upper basilar trunk saccular lesion suggesting ruptured aneurysm. However, immediate subsequent digital subtraction angiography (DSA) failed to show a vascular lesion. In one case, repeated follow up DSA was also negative. The patient was treated conservatively and discharged without any neurologic deficit. In the other case, the patient showed sudden mental deterioration on the third hospital day and her brain CT showed rebleeding. The immediate follow up DSA showed contrast stagnation in the vicinity of the upper basilar artery, suggestive of pseudoaneurysm. Double stents deployment at the disease segment was performed. Due to the frequent use of CTA, contrast extravasation is an increasingly common observation. Physicians should be aware that basilar artery extravasation can mimic the appearance of an aneurysm.

Factors Related to Subarachnoid Hemorrhage as a Cause of Out-of-Hospital Cardiac Arrest

PURPOSE: Subarachnoid hemorrhage (SAH) is a common cause of out-of-hospital cardiac arrest (OHCA). Early identification of patients with SAH induced OHCA may be helpful to emergency physicians when making therapeutic decisions. We conducted an investigation of the incidence and characteristics of patients with OHCA caused by non-traumatic SAH. METHODS: We conducted a retrospective review of cases of 236 OHCA survivors who had visited the emergency department (ED) of an urban tertiary care university hospital from January 2004 to December 2010. We excluded patients for whom there was an obvious cause or trauma. Clinical characteristics of SAH induced OHCA survivors were compared with those of SAH negative OHCA survivors. RESULTS: A total of 26 patients (19.11%) had been diagnosed with SAH. Compared with SAH negative survivors, SAH positive survivors were more likely to be female (odds ratio OR, 1.262; 95% confidence interval CI, 1.300-9.605), not to have Diabetes mellitus (OR, 0.180; 95% CI, 0.037-0.879), and to have a short duration of CPR time (OR, 1.074; 95% CI, 1.003-1.150). Results of the Cardiac Troponin T assay were less likely to be positive in patients with SAH induced OHCA, compared to those with SAH negative OHCA (OR, 0.071; 95% CI, 0.008-0.526). CONCLUSION: SAH is a more frequent cause of OHCA than originally believed. Immediate brain CT scan is useful in diagnosis of SAH when patient characteristics include: female, non diabetes mellitus, short duration of CPR time, or negative TnT.

Bilateral Vertebral Artery Dissecting Aneurysms Presenting with Subarachnoid Hemorrhage Treated by Staged Coil Trapping and Covered Stents Graft

The treatment of bilateral vertebral artery dissecting aneurysms (VADAs) presenting with subarachnoid hemorrhage (SAH) is still challenging. The authors report a rare case of bilateral VADA treated with coil trapping of ruptured VADA and covered stents implantation after multiple unsuccessful stent assisted coiling of the contralateral unruptured VADA. A 44-year-old woman was admitted to our hospital because of severe headache and sudden stuporous consciousness. Brain CT showed thick SAH and intraventricular hemorrhage. Cerebral angiography demonstrated bilateral VADA. Based on the SAH pattern and aneurysm configurations, the right VADA was considered ruptured. This was trapped with endovascular coils without difficulty. One month later, the contralateral unruptured VADA was protected using a stent-within-a-stent technique, but marked enlargement of the left VADA was detected by 8-months follow-up angiography. Subsequently two times coil packing for pseudosacs resulted in near complete occlusion of left VADA. However, it continued to grow. Covered stents graft below the posterior inferior cerebellar artery (PICA) origin and a coronary stent implantation across the origin of the PICA resulted in near complete obliteration of the VADA. Covered stent graft can be used as a last therapeutic option for the management of VADA, which requires absolute preservation of VA flow.

The Clinical Aspects of Subarachnoid Hemorrhage / 신경중재치료의학

Subarachnoid hemorrhage (SAH) is less frequent than ischemic stroke, but has a high public health relevance because it can affect young and middle-age adults, has considerable mortality and morbidity, it is treatable and preventable. Despite stable incidence, the mortality of SAH has decreased in the last two decades due to better neurosurgical techniques and neurocritical care and to advances in neuroendovascular treatment. Sudden headache is the cardinal feature. Rebleeding is the most imminent danger; a first aim is therefore occlusion of the aneurysms. Complications such as vasospasm/delayed cerebral ischemia, hydrocephalus, increased intracranial pressure, and seizures must be considered in the management of SAH. The authors reviewed the recent advances in the clinical aspects of SAH and grading system of the available evidence is included.

Clinical Analysis of Spontaneous Subarachnoid Hemorrhage with Negative Angiography / 대한뇌혈관외과학회지

OBJECTIVE: Most cases of spontaneous subarachnoid haemorrhage (SAH) are due to a ruptured cerebral aneurysm, yet sometimes the cause of bleeding can be obscure. We report here on the results of a retrospective single-center study to determine the role of the hemorrhage patterns for the patients with a negative angiogram on admission. METHODS : A total of 480 patients with spontaneous subarachnoid hemorrhage (SAH) were admitted from January 2004 to September 2008. Of these, 44 patients were included in this study because of their negative findings on their initial angiography. SAH was diagnosed by a computed tomographic scan or lumbar puncture. The clinical grade was assessed using the Hunt-Hess grading system, Fisher's grading system and the modified Rankin scale. RESULT : The overall incidence of an initially negative angiogram for patients with a spontaneous SAH was 10.2%. Based on the hemorrhage pattern on the admission CT, the most common pattern was the diffuse type (52.3%), followed by the perimesencephalic type (29.5%), the CT negative type (11.4%) and the localized non-perimesencephalic type (6.8%). The repeat angiogram revealed an aneurysm in 3 (7.7%) patients and exploration revealed a dissecting aneruysm of the vertebral artery in 1 patient. The patients with the diffuse type SAH significantly differed from the perimesencephalic group with regard to the Fisher grade (p = 0.002), the outcome at discharge (p = 0.004) and the need for EVD. CONCLUSION : Patients with SAH of an unknown cause, especially with perimesencephalic SAH, have an excellent prognosis and low mortality. We believe that digital subtraction angiogram is still the gold standard for making the diagnosis of aneurysm in patients with spontaneous SAH. A repeat angiogram is recommended for all the patients with initially angionegative SAH. For those patients with perimesencephalic SAH and a positive CSF study with a negative CT, we suggest to perform a CT angiogram as a less invasive follow-up study.

Síndrome de Hipersensibilidad a Anticonvulsivantes (SHA) / Anticonvulsivant Hypersensitivity Syndrome

El síndrome de hipersensibilidad a drogas o síndrome DRESS es una reacción rara y potencialmente fatal; se caracteriza por presentar la tríada de fiebre, rash y compromiso de órganos internos. Fenitoína, fenobarbital y carbamazepina son los anticonvulsivantes aromáticos que con más frecuencia causan esta reacción. Dicho síndrome ocurre entre la 1ra y 8va semanas después de la exposición al fármaco. La eliminación inmediata de la droga es esencial para el manejo de estos pacientes. Presentamos una paciente de sexo femenino, de 62 años, medicada con carbamazepina durante un mes, que consulta por fiebre, mal estado general y rash máculopapuloso que se generalizó hasta abarcar el 90% de la superficie cutánea.

Anticonvulsivant hypersensitivity syndrome (AHS) is a rare and potentially fatal reaction characterized by the appearance of fever, skin rash and internal organ involvement. Phenytoin, phenobarbital and carbamazepine are the most frequent aromatic anticonvulsivant causing the reaction. This syndrome occurs 1-8 weeks after the initial drug exposure.

A proposed scoring system to screen for vasospasm following aneurysmal subarachnoid hemorrhage

Vasospasm has been known to cause permanent morbidity in 40-70% of survivors who suffered from subarachnoid hemorrhage (SAH). Early recognition of vasospasm is the key to better outcome of SAH. Cerebral angiography is expensive and impractical as a monitoring tool. Transcranial Doppler is operator dependent, and not readily available. The objective of this study is to devise a non invasive tool to screen for cerebral vasospasm following SAH. The proposed vasospasm score was based on clinical and cranial CT scan features. The features are hypertension, admission World Federation of Neurosurgeons Score (WFNS), amount of blood in the cisterns and subarachnoid space, intraventricular hemorrhage and hydrocephalus. Thirty six patients with aneurismal SAH were assessed retrospectively and correlated with the angiogram for vasospasm. The patients’ vasospasm score and their corresponding sensitivity and specificity were: 1 (100%, 0%), 2 (100%, 8%), 3 (100%, 8%), 4 (100%, 8%), 5 (91%, 46%), 6 (74%, 85%), 7 (48%, 85%), 8 (26%, 23%), 9 (3%, 100%), 10 (4%, 100%). A receiver operator characteristic curve was constructed that yielded a cut-off score of 6. The score of 6 was a good trade-off between sensitivity (74%) and specificity (85%). A clinical vasospasm score was proposed to screen for vasospasm after SAH. A score of 4 to 6 was found to correlate with angiographic vasospasm. Prospective study is required to validate the scoring system.

Effects of Maternal Folic Acid Nutritional Status on the Expression of Myelin Basic Protein in the Offspring

Myelin basic protein (MBP ), a major structural protein of the myelin, is thought to be important for the maintenance of myelin in the central nervous system (CNS ). We investigated the effect of maternal folic acid nutritional status on the folate level and the synthesis of MBP in the offspring. In order to test this hypothesis, female Sprague-Dawley rats were fed either folic acid sufficient (8 mg/kg diet )or deficient (0 mg/kg diet )diet from 2 wks prior to the mating throughout the entire pregnancy, lactation and weaning period. We examined plasma folate level by the radioimmunoassay and homo-cysteine level by HPLC, respectively. The MBP expression was measured by the western blot analysis. The maternal folic acid deficiency decreased plasma folate level with a concomitant increase in plasma homocysteine level in their offspring. The maternal folic acid deficiency decreased hepatic levels of SAM and SAM/SAH ratio with a concomitant increase in hepatic levels of SAH and the MBP expression of spinal cord in their offspring at 7 wks of age. These results suggest that maternal folic acid nutritional status affect plasma folate and homocysteine level in their offspring. Moreover, the maternal folic acid deficiency might inhibit the MBP expression of the spinal cord and disrupt many other vital CNS reac-tions in their offspring.

Homocysteine-mediated Aberrant DNA Methylation in Vascular Smooth Muscle Cells and Its Potential Pathogenic Mechanism / 生物化学与生物物理进展

Hyperhomocysteinemia, which is an independent risk factor for atherosclerosis, may cause aberrant methylation and dysregulation of gene expression, but the characteristics of the aberrant methylation and its key links involved in its pathogenic mechanisms are still poorly understood. The effect of hyperhomocysteine on DNA methylation in vascular smooth muscle cells, its characteristics and the underlying mechanism of Hcy-induced changing in DNA methylation patterns were investigated. Clinical relevant concentrations of homocysteine was added into the cultured vascular smooth muscle cells of the Homo sapien umbilical vein for 24 h. The level of SAM and SAH was detected by HPLC. The activity of SAH Hydrolase was detected by real-time quantitative reverse transcription-PCR and Western blotting analysis. The level and patterns of DNA methylation were measured by endogenous C-5 DNA methyltransferase(C-5 MT-ase) activity and capacity of genomic DNA to accept methyl groups and methylation-dependent restriction analysis. The results indicated that an increased Hcy concentration induced elevated SAH, declined SAM and the ratio of SAM/SAH, reduced expression of SAH Hydrolase, but increased activity of C-5MT-ase. The methylation status of gDNA analyzed by methyl-accepting capacity of gDNA uncovered a demethylation process in gDNA, or homocysteine-caused hypomethylation in gDNA.With different methylation-dependent restriction endonucleases, the aberrant demethylation was found to prefer C↓CGG sequences to CpG islands. The impacts of different dosage of Hcy showed that the varied detrimental effects of Hcy could be attributed to different concentrations via different mechanisms. In mild and moderate hyperhomocysteinemia, the Hcy may primarily influence the epigenetic regulation of gene expression through the interference of transferring methyl-group metabolism, while in more higher Hcy concentration, the notorious impacts may be more directly caused via oxidative stress, apoptosis, inflammation etc.

The Incidence of Aneurysmal Subarachnoid Hemorrhage in Youngdong District, Korea

OBJECTIVE: The purpose of this study is to investigate the incidence of aneurysmal subarachnoid hemorrhage (SAH) in Youngdong district for 10 years. METHODS: From Jan. 1997 to Dec. 2006, 732 patients (327 males, 405 females, mean age: 54.8+/-13.1 years) with spontaneous SAH were admitted to our hospital. We reviewed the medical records and radiological findings regarding to the ictus of SAH, location and size of the ruptured aneurysms, Hunt-Hess grade and Fisher grade on admission, personal details such as address, age, and sex, and previous history of medical diseases. RESULTS: In these 732 patients, 672 cases were confirmed as aneurysmal SAH. Among them, 611 patients (262 males, 349 females, mean age: 54.9+/-13.2 years) came from Youngdong district. The average crude annual incidence of aneurysmal SAH for men, women, and both sexes combined in Youngdong district was 7.8+/-1.7, 10.5+/-2.7, and 9.1+/-2.1 per 100,000 population, respectively. Because of the problems related to the observation period and geographical confinement, it was suspected that the representative incidence of aneurysmal SAH in Youngdong district should be made during the later eight years in six coastal regions. Therefore, the average age-adjusted annual incidence for men, women, and both sexes combined was 8.8+/-1.4, 11.2+/-1.3 and 10.0+/-1.0, respectively in the coastal regions of Youngdong district from 1999 to 2006. CONCLUSION: In overall, our results on the incidence of aneurysmal SAH was not very different from previous observations from other studies.

A Study of the Effect of Acute Subarachnoid Hemorrhage on Left Ventricular Function and the Relationship Between Acute Subarachnoid Hemorrhage and Plasma Brain Natriuretic Peptide / 医学研究杂志

0.05).②The mean of SV, the mean of CO and the mean of CI in acute SAH group were lower than those in healthy persons group respectively (33.46?11.33 vs 52.67?12.46,P

Ruptured Aneurysm of the Ophthalmic Artery

Aneurysms arising from the ophthalmic artery itself are very rare compared with aneurysms originating from the bifurcation of the ophthalmic artery and carotid artery. There was only one reported case of a ruptured aneurysm of the ophthalmic artery itself. We discuss clinical significance of an aneurysm at this site, as well as the role of three dimentional image of multislice computed tomography angiogram(3D-image of MCTA) in determining the cause of subarachnoid hemorrhage(SAH).

"Misery Collaterals" as Poor Angiographic Findings: Definition, Classification, and Practical Application

OBJECTIVE: Unique internal carotid artery angiographic findings have been found especially in very poor grade aneurysmal subarachnoid hemorrhage(SAH) patients before and during the endovascular coiling. The author investigates their patterns and classifies them into four subtypes. METHODS: Among Hunt&Hess grade IV, V SAH patients, the author could gather eight patients who showed abnormal intracranial circulation in cerebral catheter-based angiography. RESULTS: The author introduces new term 'misery collaterals' first and has classified them into four types with the case illustrations. Type 1 is the worst condition defined as almost no intracranial circulation. Type 2 is the condition of little intracranial circulation with contrast filling just only at vessels of brain base, type 3 is of no or little cortical circulation with contrast filling at bilateral large vessels of brain base through circle of Willis channel and type 4 is of visible bilateral cortical circulation but delayed intracranial circulation time. The prognosis of these eight patients showed misery collaterals were disappointed. CONCLUSION: These finding can be used as the supportive information in deciding a management plan in poor grade SAH patients.

Does Age Influence the Poor Prognosis after Aneurysmal SAH Surgery in Elderly Patients?

OBJECTIVE: The incidence of aneurysmal subarachnoid hemorrhage has been increasing. At the same time, surgical results for elderly patients are unsatisfactory and no guidelines of treatment are available. We carried out a study comparing variable factors and surgical results between young and old age groups to find ways to improve prognosis. METHODS: A retrospective study was carried out on 754 patients who were operated on between 1990 and 2004 by the same surgeon in our hospital. The patients were divided into seven groups according to age: 93 patients below 40 years of age (Group I), 419 patients aged 40~59 (Group II), 115 patients aged 60~64 (Group III), 82 patients aged 65~69 (Group IV), 28 patients aged 70~74 (Group V), 12 patients aged 75~79 (Group VI) and 5 patients over the age of 80 (Group VII). We then checked their medical history, Fisher's grade, Hunt-Hess grade, postoperative complications, and Glasgow Outcome Scale. RESULTS: Age was not a statistically significant factor among patients below 70 years of age (P value> or =0.05). But for those aged 70 and older, the age factor had a statistical value (P value< or =0.001). In addition, there was a close correlation between Hunt-Hess grade IV and V patients, and those with vasospasm, and hydrocephalus after surgery, with poor prognosis in elderly patients as well as young patients (P value< or =0.001). CONCLUSION: Advanced age (under the age of 70) dose not precluded adequate surgical treatment in patient with AN SAH, and we should be also alert to preventable causes of delayed neurological deterioration for improving the outcome in all elderly groups.

Usefulness of CT Perfusion in the Postoperative Evaluation of Ruptured Aneurysm / 대한뇌혈관외과학회지

OBJECTIVE: Our goal was to evaluate the usefulness of CT perfusion (CTP) in early detection of the post operative cerebral ischemia, alteration of treatment modality and patient prognosis in cerebral aneurysm patients. METHODS: 24 patients who underwent either surgical operation or endovascular coiling for ruptured aneurysms were selected. All patients undertook an angiogram, conventional CT, and CTP scan immediately following surgical operation or endovascular coiling. All patients performed a CT 2 weeks after treatment to evaluate possible development of a cerebral infarction. Postoperative CT results of patients with abnormal postoperative CTP scan findings were compared, and these results were compared with the CT results and clinical symptoms of patients who developed infarction or not. RESULTS: Of the 24 patients evaluated, 11 patients showed abnormal findings on CTP. 9 patients were diagnosed with cerebral infarction through a CT scan done 2 weeks after treatment; all exhibited abnormal CTP results immediately after treatment. Abnormal CTP findings were divided into two groups; patients with abnormal CBF and MTT maps, but with normal CBV maps, and patients with abnormal CBF, CBV and MTT maps. A correlation was seen between abnormality on CBV maps and cerebral infarction. Patients with abnormal CTP findings also exhibited poorer prognostic value. CONCLUSION: Postoperative CTP in ruptured aneurysm patients is a very useful and objective tool in evaluating abnormal cerebral hemodynamics. The CBV map of CTP is the most precisely predictable value of postoperative patient's status and alteration of treatement modality.