Role of inflammation (leukocyte-endothelial cell interactions) in vasospasm after subarachnoid hemorrhage

BackgroundDelayed vasospasm is the leading cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). This phenomenon was first described more than 50 years ago, but only recently has the role of inflammation in this condition become better understood.MethodsThe literature was reviewed for studies on delayed vasospasm and inflammation.ResultsThere is increasing evidence that inflammation and, more specifically, leukocyte-endothelial cell interactions play a critical role in the pathogenesis of vasospasm after aSAH, as well as in other conditions including meningitis and traumatic brain injury. Although earlier clinical observations and indirect experimental evidence suggested an association between inflammation and chronic vasospasm, recently direct molecular evidence demonstrates the central role of leukocyte-endothelial cell interactions in the development of chronic vasospasm. This evidence shows in both clinical and experimental studies that cell adhesion molecules (CAMs) are up-regulated in the perivasospasm period. Moreover, the use of monoclonal antibodies against these CAMs, as well as drugs that decrease the expression of CAMs, decreases vasospasm in experimental studies. It also appears that certain individuals are genetically predisposed to a severe inflammatory response after aSAH based on their haptoglobin genotype, which in turn predisposes them to develop clinically symptomatic vasospasm.ConclusionBased on this evidence, leukocyte-endothelial cell interactions appear to be the root cause of chronic vasospasm. This hypothesis predicts many surprising features of vasospasm and explains apparently unrelated phenomena observed in aSAH patients. Therapies aimed at preventing inflammation may prevent and/or reverse arterial narrowing in patients with aSAH and result in improved outcomes.     

Bioequivalence study of generic amlodipine in healthy Thai male volunteers

SUBJECTS, MATERIAL AND METHODS: To determine the bioequivalence of 10 mg generic amlodipine in healthy male volunteers, the reference and the test formulations were administered as a single oral dose after overnight fasting in a crossover study separated by 2-week washout interval. After dosing, serial blood samples were collected for a period of 144 h. Plasma amlodipine concentrations were determined by LC-MS/MS and the pharmacokinetic parameters were analyzed by non-compartmental analysis. RESULTS: The mean elimination half-life (t1/2) for the test (40 h) and the reference (44 h) were within the values previously reported. The rate of absorption reflected by tmax had a difference of -0.33 h, with a 90% CI of (-1.52)-0.85 (acceptable range +/- 1.3). Although the tmax of the test (5 h) was faster than the reference (6 h), the mean (90% CI) of the AUC(0-infinity) and Cmax ratios Test/Reference were 0.91 (0.87-0.97) and 1.01 (0.93-1.09), respectively. These values were within the range of 0.80-1.25, thus, the study demonstrated the bioequivalence of the 2 formulations.     

The human subventricular zone: a source of new cells and a potential source of brain tumors

The mammalian brain has been perceived as a quiescent organ incapable of postnatal neurogenesis for many years. Most recently, several studies have demonstrated that the adult mammalian brain is indeed capable of neurogenesis and that the process is primarily confined to the subventricular zone (SVZ) of the forebrain and the subgranular zone (SGZ) of the hippocampus. Of these regions, the SVZ is the largest niche of neurogenesis in the adult mammalian brain. Within this niche resides a subpopulation of astrocytes with stem cell-like features of self-renewal and multipotentiality. Interestingly, there is also a subpopulation of cells within brain tumors that possess these same characteristics. Based on these findings, the emerging hypothesis is that brain tumor stem cells may be derived from neural stem cells and that both of these populations may originate from the SVZ. This possible connection stresses the importance of studying and understanding the role that the human SVZ plays in not only harboring neural and brain tumor stem cells, but how this microenvironment may support both neurogenesis and tumorigenesis. Furthermore, the obvious differences in the SVZ between humans and other animals make it important to understand the human model when studying human disease. Such an understanding may lead to novel therapeutic strategies for both neurodegenerative diseases and currently intractable brain tumors.     

Preservation of glial cytoarchitecture from ex vivo human tumor and non-tumor cerebral cortical explants: A human model to study neurological diseases

For the human brain, in vitro models that accurately represent what occurs in vivo are lacking. Organotypic models may be the closest parallel to human brain tissue outside of a live patient. However, this model has been limited primarily to rodent-derived tissue. We present an organotypic model to maintain intraoperatively collected human tumor and non-tumor explants ex vivo for a prolonged period of time ( approximately 11 days) without any significant changes to the tissue cytoarchitecture as evidenced through immunohistochemistry and electron microscopy analyses. The ability to establish and reliably predict the cytoarchitectural changes that occur with time in an organotypic model of tumor and non-tumor human brain tissue has several potential applications including the study of cell migration on actual tissue matrix, drug toxicity on neural tissue and pharmacological treatment for brain cancers, among others.     

Minimizing OCT quantification error via a surface-tracking imaging probe

OCT-based quantitative tissue optical properties imaging is a promising technique for intraoperative brain cancer assessment. The attenuation coefficient analysis relies on the depth-dependent OCT intensity profile, thus sensitive to tissue surface positions relative to the imaging beam focus. However, it is almost impossible to maintain a steady tissue surface during intraoperative imaging due to the patient’s arterial pulsation and breathing, the operator’s motion, and the complex tissue surface geometry of the surgical cavity. In this work, we developed an intraoperative OCT imaging probe with a surface-tracking function to minimize the quantification errors in optical attenuation due to the tissue surface position variations. A compact OCT imaging probe was designed and engineered to have a long working distance of ∼ 41 mm and a large field of view of 4 × 4 mm² while keeping the probe diameter small (9 mm) to maximize clinical versatility. A piezo-based linear motor was integrated with the imaging probe and controlled based upon real-time feedback of tissue surface position inferred from OCT images. A GPU-assisted parallel processing algorithm was implemented, enabling detection and tracking of tissue surface in real-time and successfully suppressing more than 90% of the typical physiologically induced motion range. The surface-tracking intraoperative OCT imaging probe could maintain a steady beam focus inside the target tissue regardless of the surface geometry or physiological motions and enabled to obtain tissue optical attenuation reliably for assessing brain cancer margins in challenging intraoperative settings.     

Spinal deformity after resection of cervical intramedullary spinal cord tumors in children

Objective Progressive spinal deformity after cervical intramedullary spinal cord tumor (IMSCT) resection requiring subsequent fusion occurs in many cases among pediatric patients. It remains unknown which subgroups of patients represent the greatest risk for progressive spinal deformity. Materials and methods The data for 58 patients undergoing surgical resection of cervical IMSCT at a single institution were retrospectively collected and analyzed for development of progressive spinal deformity requiring fusion. The association of all clinical, radiographic, and operative variables to subsequent progressive spinal deformity as a function of time was assessed via Kaplan–Meier plots and Log-rank and Cox analyses. Results Mean age at the time of surgery was 11 ± 6years. Eleven (19%) patients required subsequent fusion for progressive spinal deformity at a median [interquartile range (IQR)] of 4 (2–6) years after IMSCT resection. Five (36%) of 14 patients with preoperative scoliosis or loss of lordosis developed postoperative progressive spinal deformity compared to only 6 (13%) of 44 patients with normal preoperative sagittal and coronal balance, p = 0.06. Patients <13years of age were more than three times more likely to develop postoperative progressive deformity, p = 0.05. Decompression spanning both the axial cervical spine (C1–C2) and the cervico–thoracic junction (C7–T1) increased the risk for progressive spinal deformity fourfold, p = 0.04. Number of spinal levels decompressed, revision surgery, radiotherapy, involvement of C1–C2 or C7–T1 alone in the decompression, or any other recorded variables were not associated with progressive postoperative spinal deformity. Conclusion Patients possessing one or more of these characteristics should be monitored closely for progressive spinal deformity after surgery.     

Alpha 1-antichymotrypsin contributes to stem cell characteristics and enhances tumorigenicity of glioblastoma

BackgroundGlioblastomas (GBMs) are the main primary brain tumors in adults with almost 100% recurrence rate. Patients with lateral ventricle proximal GBMs (LV-GBMs) exhibit worse survival compared to distal locations for unknown reasons. One hypothesis is the proximity of these tumors to the cerebrospinal fluid (CSF) and its chemical cues that can regulate cellular phenotype. We therefore investigated the role of CSF on GBM gene expression and the role of a CSF-induced gene, SERPINA3, in GBM malignancy in vitro and in vivo.MethodsWe utilized human CSF and GBM brain tumor-initiating cells (BTICs). We determined the impact of SERPINA3 expression in glioma patients using The Cancer Genome Atlas (TCGA) database. SERPINA3 expression changes were evaluated at mRNA and protein levels. The effects of knockdown (KD) and overexpression (OE) of SERPINA3 on cell migration, viability and cell proliferation were evaluated. Stem cell characteristics on KD cells were evaluated by differentiation and colony formation experiments. Tumor growth was studied by intracranial and flank injections.ResultsGBM-CSF increased BTIC migration accompanied by upregulation of the SERPINA3 gene. In patient samples and TCGA data, we observed SERPINA3 to correlate directly with brain tumor grade and indirectly with GBM patient survival. SERPINA3 KD induced a decrease in cell proliferation, migration, invasion, and stem cell characteristics, while SERPINA3 OE increased cell migration. In vivo, SERPINA3 KD BTICs showed increased survival in a murine model.Conclusions SERPINA3 plays a key role in GBM malignancy and its inhibition results in a better outcome using GBM preclinical models.     

Potential risk factors for psychiatric disorders in patients with headache

Background.— Psychiatric comorbidities are common among patients with headache. These can compromise the quality of life of patients and may affect the result of treatment. No available systematic study concerning this problem has been conducted in Thailand. Objective.— The study aimed to determine the prevalence and risk factors of psychiatric disorders in patients with headache in tertiary care facility. Methods.— The study was conducted at the Headache Clinic, King Chulalongkorn Memorial Hospital in Bangkok, Thailand. One hundred and thirteen patients were enrolled. Diagnosis of headache was made based on International Classification of Headache Disorders II system. Mental disorders were assessed using Primary Care Evaluation of Mental Disorders. Other possible risk factors were extracted using significant physical symptoms count and accumulated risk for mental disorder. Results.— Of the 113 samples analyzed, the prevalence of depression, anxiety, and somatoform disorder was found to be 29.2%, 9.7%, and 27.4%, respectively. No definite relationship between headache types and mental disorders was observed. High number of significant physical complaints and health concerns significantly increased the risk for depression (OR = 4.6, 95% CI = 1.6 to 13.5) while the level of possible risk for mental disorder was associated with an increased risk for somatoform disorder (OR = 1.6, 95% CI = 1.2 to 2.2). Conclusion.— The study confirmed high prevalence of psychiatric comorbidities in patients with headache. The results of this study will raise the awareness of physicians to possible underlying mental disorders in patients with headache and facilitate appropriate treatment or psychiatric referral.