Novel Animal Model of Spontaneous Cerebral Petechial Hemorrhage Using Focused Ultrasound in Rats.

Background and Objectives: Petechial cerebral hemorrhages can be caused by various factors, such as traumas, cerebral infarctions, and aging, and is related to the disruption of the blood-brain barrier or the cellular damage of blood vessels. However, there is no animal model that recapitulates cerebral petechial hemorrhages. Materials and Methods: Here, we implemented a petechial hemorrhage using a novel technology, i.e., microbubble-assisted focused ultrasound (MB + FUS). Results: This method increases the permeability of the blood-brain barrier by directly applying mechanical force to the vascular endothelial cells through cavitation of the microbubbles. Microbubble-enhanced cavitation has the advantage of controlling the degree and location of petechial hemorrhages. Conclusions: We thus generated a preclinical rat model using noninvasive focal MB + FUS. This method is histologically similar to actual petechial hemorrhages of the brain and allows the achievement of a physiologically resembling petechial hemorrhage. In the future, this method shall be considered as a useful animal model for studying the pathophysiology and treatment of petechial cerebral hemorrhages.

Clinical significance of vitamin D in idiopathic normal pressure hydrocephalus.

BACKGROUND: Although recent studies show vitamin D deficiency is associated with cognitive decline, urinary incontinence, and gait instability, there has been no study on the effect of vitamin D on idiopathic normal pressure hydrocephalus (iNPH) characterized by the classic symptom triad of cognitive decline, urinary incontinence, and gait instability. We investigated the clinical significance of vitamin D in patients with iNPH. METHODS: Between 2017 and 2020, 44 patients who underwent ventriculoperitoneal shunt surgery were divided into low (< 15 ng/mL) and high (≥ 15 ng/mL) vitamin D groups according to the concentration of 25(OH)D, an effective indicator of vitamin D status. They were respectively evaluated according to clinical and radiological findings. RESULTS: The low vitamin D group (n = 24) showed lower preoperative cognition compared to the high vitamin D group (n = 20) in terms of Korean-Mini Mental Status Examination (K-MMSE) and iNPH grading scale (iNPHGS) (K-MMSE: 20.5 ± 5.4 versus 24.0 ± 4.5, p = 0.041; iNPHGS cognitive score: 2 ± 0.9 versus 1 ± 0.6, p = 0.025). And the low vitamin D group showed pre- and postoperatively more severe urinary incontinence (preoperative iNPHGS urinary score: 1 ± 1.0 versus 0 ± 0.9, p = 0.012; postoperative iNPHGS urinary score:1 ± 1.0 versus 0 ± 0.9, p = 0.014). The score of narrow high-convexity sulci for the low vitamin D group was lower (low vitamin D group: 1 ± 0.7 versus high vitamin D group: 2 ± 0.4, p = 0.031). CONCLUSION: Lower concentration of vitamin D in iNPH may be related to lower preoperative cognition, pre- and postoperative urinary incontinence, and brain morphological change.

Progressively enlarging childhood chronic subdural hematoma surgically treated 26 years after diagnosis.

Pediatric chronic subdural hematoma (CSDH) is a relatively common disorder. Treatment often requires burr hole drainage or subduroperitoneal shunt placement; some patients are managed conservatively. However, the long-term outcome of untreated pediatric CSDH is unknown. The authors report a case of a huge, progressively enlarging subdural granuloma that was surgically treated 26 years after the initial diagnosis of CSDH. This 30-year-old male patient presented with worsening intermittent atonic seizure-like movements, which had been noted since he was 4 years old. At that time, the patient was diagnosed with CSDH at an outside hospital, but an operation was refused by the parents. Magnetic resonance imaging (MRI) performed at 23 years of age showed a huge subdural mass on the right frontoparietal region and a smaller mass on the left side with a significant midline shift. Upon presentation at the age of 30, MRI revealed worsening of the right subdural mass and midline shift. Subsequently, the patient underwent craniotomy and subtotal removal of the mass and capsule. The volume of the content was approximately 430 cc. Untreated pediatric CSDH can grow progressively, even over several decades. Patients with CSDH, especially those managed conservatively, should be closely monitored for worsening symptoms over a long-term follow-up period.

Border Zone Maybe Correlated with Radiation Necrosis After Radiosurgery in Metastatic Brain Tumor.

BACKGROUND: Radiation necrosis (RN) after stereotactic radiosurgery (SRS) in brain metastases has been extensively evaluated, and RN is correlated with various risk factors. However, no study comprehensively analyzed the correlation between RN and the border zones of the brain that are vulnerable to ischemia. We hypothesized that patients with tumors in the border zone are at high risk of RN. Hence, the current study aimed to assess the correlation between border zone lesions and RN, with consideration of other predetermined factors. METHODS: This retrospective study included 117 patients with 290 lesions who underwent Gamma Knife SRS. Radiological and clinical analyses were performed to identify factors possibly correlated with RN. Notably, the lesion location was classified into 2 groups (border zone and nonborder zone) based on the blood supply. RESULTS: In total, 22 (18.8%) patients with 22 (7.5%) lesions developed RN. Univariate analysis revealed a significant correlation between RN and external border zone lesions, second course of SRS administered at the same site of the previous SRS, prescribed dose, and tumor volume. Multivariate analysis showed that border zone lesions, second course of SRS at the same site of the previous SRS, and tumor volume were significantly correlated with RN. CONCLUSIONS: Patients with tumors in the border zone are at high risk of RN. The potential risks of RN can be attributed hypothetically to hypoperfusion. Hence, the association between RN and border zone lesions seems reasonable.

Unexpected shunt-dependent hydrocephalus after unruptured aneurysm surgery-a case report.

A chronic hydrocephalus after unruptured aneurysm surgery is an extremely rare condition. Its etiology and pathophysiology are also unclear. We report a case of chronic hydrocephalus in a patient who underwent permanent shunt placement after unruptured aneurysm clipping surgery. A 65-year-old man developed chronic hydrocephalus requiring shunt placement after clipping surgery of left anterior cerebral artery aneurysm and right middle cerebral artery aneurysm. This case shows that chronic hydrocephalus is a possible complication of unruptured aneurysm surgery, which can be resolved with an appropriate shunt operation.

Venous ectasia preceding intra-tumoral hemorrhage in a case of gliosarcoma with transverse sinus involvement.

Although intratumoral hemorrhage is common in patients with malignant brain tumors, reports on its clinical course are scarce. This report presents a rare case of a patient with intratumoral hemorrhage with gliosarcoma invading the venus sinus. This invasion and a small draining vein were observed at diagnosis. Magnetic resonance imaging performed 1 week later showed new-onset venous ectasia, which caused intratumoral hemorrhage. This case provides insight into the mechanisms underlying intratumoral hemorrhage and highlights the emergence of new intratumoral vasculature as a potential warning sign for hemorrhage.

Development of an Angiography Guide Indicator for Stereotactic Radiosurgery for High Precision.

BACKGROUND: Stereotactic radiosurgery (SRS) is effectively used for treating various cerebrovascular diseases, including arteriovenous malformations. As image-based surgery is the gold standard technique in SRS, the quality of stereotactic angiography images greatly influences the surgical approach for cerebrovascular diseases. Despite several studies in the relevant literature, research on auxiliary devices, including angiography indicators used for cerebrovascular disease surgeries, is limited. Thus, the development of angiographic indicators may provide meaningful data for stereotactic surgery. METHODS: A centerline was drawn, and a guideline was attached such that the "+" and "X" centers of the existing angiography guide indicator intersect. Further, a guideline wire connecting "+" and "X" was fixed using a tape. Based on the presence or absence of the guide indicator, angiography anterior-posterior (AP) and lateral (LAT) images were taken 10 times each, and statistical analysis was performed. RESULTS: The average and standard deviation of the conventional AP and LAT indicators were 10.22 ± 0.53 mm and 9.02 ± 0.33 mm, and those of the developed AP and LAT indicators were 10.3 ± 0.57 mm and 8.92 ± 0.23 mm, respectively. CONCLUSIONS: The results confirmed that the use of the lead indicator developed in this study provides higher accuracy and precision compared to that of the use of the conventional indicator. Furthermore, the developed guide indicator may provide meaningful information during SRS.

Optofluidic particle manipulation in a liquid-core/liquid-cladding waveguide.

This paper describes a method for particle manipulation in a liquid-core/liquid-cladding optical waveguide system. Step-index and graded-index waveguides were modeled with consideration for, respectively, miscible and immiscible core and cladding fluids. The characteristic motions of four different particles with refractive indices of 1.59, 1.48, 1.37, and 1.22 were examined. The guided beam was assumed to be Gaussian in shape. Our results showed that high-refractive-index particles converged at the center of the core fluid due to a positive gradient force, whereas low-refractive-index particles converged at the flow periphery. The nonlinearity of the particle motion increased as the flow velocity and the guided beam waist decreased and the laser power and the particle size increased. The initial beam waist of the guided beam in the graded-index waveguide did not significantly affect the characteristics of the particle motion due to the effects of diffusion.

Behavior of double emulsions in a cross-type optical separation system.

The behavior of double emulsions in a cross-type optical particle separation system was studied for different combinations of refractive indices and different inner and outer layer radii. The radii and refractive indices of the double emulsions were easily adjusted by taking advantage of the coflowing geometry of a cross-type optical particle separation device. An analytical expression of the optical forces on a pair of concentric spheres was derived using the photon stream method in the ray optics regime. The predicted trajectories of the double emulsions by the optical force agreed well with the experimental data. This work has potential uses in cell separation by morphometry, drug delivery vehicle, and emulsion-based biomedical applications.

Development of an Animal Stereotactic Device for Preclinical Research on Tumor Response After Stereotactic Radiosurgery.

BACKGROUND: In gamma knife radiosurgery, the tumor response to radiation is an important predictor of clinical treatment results. Since brain tumors have different characteristics and growth patterns, depending on the type, the tumors' response to radiation are also different. Compared with various other clinical treatments, there is a dearth of research on the development of gamma knife-magnetic resonance imaging (MRI) preclinical experimental equipment. Hence, the identification of preclinical equipment necessity for experimental animals will provide meaningful data for the provision of clinical assistance to humans. OBJECTIVES: A device for stereotactic radiosurgery capable of MRI in small animals was developed. The feasibility of creating a preplan by means of small animal images was then assessed. METHODS: A device for stereotaxic surgery of small animals using a 48-channel MRI coil was developed using a 3 dimensional printer. Rat brain-MRI images were obtained with a 3.0 T MRI scanner using a multi-channel coil. The acquired MRI images were transferred to a GammaPlan workstation to establish a preplan. RESULTS: To gamma rays to the targeted site on animals, a positioning device combined with a G-frame was mounted on a gamma knife. Planning of radiosurgery based on MRI images became possible with GammaPlan workstations. CONCLUSIONS: Preclinical experiments using small animals are possible with the use of stereotactic devices. In clinical treatment, preclinical experimental results will provide meaningful information.

Frictional force analysis of stent retriever devices using a realistic vascular model: Pilot study.

Objective: To date, no vascular model to analyze frictional forces between stent retriever devices and vessel walls has been designed to be similar to the real human vasculature. We developed a novel in vitro intracranial cerebrovascular model and analyzed frictional forces of three stent retriever devices. Methods: A vascular mold was created based on digital subtraction angiography of a patient's cerebral vessels. The vascular model was constructed using polydimethylsiloxane (PDMS, Dow Corning, Inc.) as a silicone elastomer. The vascular model was coated on its inner surface with a lubricating layer to create a low coefficient of friction (~0.037) to closely approximate the intima. A pulsatile blood pump was used to produce blood flow inside the model to approximate real vascular conditions. The frictional forces of Trevo XP, Solitaire 2, and Eric 4 were analyzed for initial and maximal friction retrieval forces using this vascular model. The total pulling energy generated during the 3 cm movement was also obtained. Results: Results for initial retrieval force were as follows: Trevo, 0.09 ± 0.04 N; Solitaire, 0.25 ± 0.07 N; and Eric, 0.33 ± 0.21 N. Results for maximal retrieval force were as follows: Trevo, 0.36 ± 0.07 N; Solitaire, 0.54 ± 0.06 N; and Eric, 0.80 ± 0.13 N. Total pulling energy (N·cm) was 0.40 ± 0.10 in Trevo, 0.65 ± 0.10 in Solitaire, and 0.87 ± 0.14 in Eric, respectively. Conclusions: Using a realistic vascular model, different stent retriever devices were shown to have statistically different frictional forces. Future studies using a realistic vascular model are warranted to assess SRT devices.

Simultaneous measurements of cytoplasmic viscosity and intracellular vesicle sizes for live human brain cancer cells.

Intracellular vesicles, comprised of protein clusters, were individually tracked inside human brain cancer cells and characterized to simultaneously determine the average vesicle size and effective cytoplasmic viscosity. The cells were transfected with a TGF-ß superfamily gene, non-steroidal anti-inflammatory drug-Activated Gene-1 (NAG-1) tagged with green fluorescent proteins (GFPs). Using total internal reflection fluorescent microscopy (TIRFM) the individual movements of the vesicles were categorized into either Brownian, caged, or directional type motion. In the near-field region confined by the evanescent wave field of TIRFM, the hindrance of these vesicles was created by interactions with the glass coverslip and/or sub-cellular structures. Measured particle motions were compared with theoretical predictions of hindered motion to estimate the unknown size and viscosity parameters using a nonlinear regression technique. For the tested human brain cancer cells, the average vesicle size and effective intracellular fluid viscosity were calculated to be 496 nm and 0.068 Pa s, respectively. This finding suggests that most of the hindrance experienced by vesicles can be due to non-hydrodynamic interactions with microtubules and other intracellular structures. It should be also noted that this method provides a way to examine changes in vesicle size due to outside stimulus such as drug interaction, cytotoxicity, etc., unlike standard measurement techniques which require fixing the cells themselves.

Bead packing and release using flexible polydimethylsiloxane membrane for semi-continuous biosensing.

The continuous or semi-continuous biosensing of systemic inflammatory responses is important both during and after cardiopulmonary bypass (CPB) procedures. A bead packing and release method, which is able repetitively to capture and release receptor-coated beads within microfluidic channels, is herein advanced for use in semi-continuous biosensing. The receptor-coated beads are compacted and concentrated at specific locations in the device using an elastomeric valve. This concentration creates a localized bioreactor in which the binding of the antigen with the functionalized beads can be made more effective. After the reaction and detection have taken place, the beads can be released and a new assay carried out. We demonstrated the operation of our device using streptavidin-coated beads and biotin-4-fluorescein (B4F). The high sensitivity of the device allows it to detect a B4F concentration of 50 pg/mL after an incubation time of 5 min. We also tested our device in the semi-continuous immunoassay of interleukin (IL)-6, which is one of the proinflammatory cytokines. The assay demonstrated the linear dependence of the intensity of fluorescence at concentrations of IL-6 from 10 to 250 pg/mL, which is a physiologically important range for CPB procedures.

Bridging the intracranial pressure gap: a smooth transition strategy for slit ventricle syndrome.

Slit ventricle syndrome (SVS) is a well-known complication of long-standing shunts. Patients develop intermittent severe headache, vomiting with other symptoms of increased intra-cranial pressure. Brain computed tomography (CT) usually reveals slit-like ventricles with nearly obstructed proximal catheters. Treatment for SVS usually involves upgrading the shunt valve pressure setting. Currently, many patients carry programmable shunts and pressure setting can be adjusted noninvasively. However, when the programmable valve pressure setting is upgraded, some patients with SVS experience worsened symptoms. This is caused by the time gap between ICP increase and real ventricular expansion (and freeing proximal catheter) after shunt upgrading. Therefore, it is important to control a patient's symptoms during the transition period. We report our experience in controlling ICP in a patient with SVS using external ventricular drainage.

Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull.

Methods to improve drug delivery efficiency through blood-brain barrier disruption (BBBD) based on microbubbles and focused ultrasound (FUS) are continuously being studied. However, most studies are being conducted in preclinical trial environments using small animals. The use of the human skull shows differences between the clinical and preclinical trials. BBBD results from preclinical trials are difficult to represent in clinical trials because various distortions of ultrasound by the human skull are excluded in the former. Therefore, in our study, a clinical validation platform based on a preclinical trial environment, using a human skull fragment and a rat model, was developed to induce BBBD under conditions similar to clinical trials. For this, a human skull fragment was inserted between the rat head and a 250 kHz FUS transducer, and optimal ultrasound parameters for the free field (without human skull fragment) and human skull (with human skull fragment) were derived by 300 mVpp and 700 mVpp, respectively. BBBD was analyzed according to each case using magnetic resonance images, Evans blue dye, cavitation, and histology. Although it was confirmed using magnetic resonance images and Evans blue dye that a BBB opening was induced in each case, multiple BBB openings were observed in the brain tissues. This phenomenon was analyzed by numerical simulation, and it was confirmed to be due to standing waves owing to the small skull size of the rat model. The stable cavitation doses (SCDh and SCDu) in the human skull decreased by 13.6- and 5.3-fold, respectively, compared to those in the free field. Additionally, the inertial cavitation dose in the human skull decreased by 1.05-fold compared to that of the free field. For the histological analysis, although some extravasated red blood cells were observed in each case, it was evaluated as recoverable based on our previous study results. Therefore, our proposed platform can help deduct optimal ultrasound parameters and BBBD results for clinical trials in the preclinical trials with small animals because it considers variables relevant to the human skull.

Effect of Cadherin-11 Expression on the Prognosis of a Newly Diagnosed Primary Glioblastoma.

BACKGROUND: Cadherin-11, a cell-to-cell adhesion molecule, is associated with higher tumor grade and decreased patient survival. The purpose of this study was to investigate the clinical significance of cadherin-11 expression in the progression and prognosis of a newly diagnosed primary glioblastoma (GBL). METHODS: Between 2007 and 2016, 52 out of 178 patients diagnosed with a GBL and satisfied the following criteria: 1) a new primary GBL, 2) gross-total resection, 3) immunohistochemically-available tissue, and 4) standardized adjuvant treatment. RESULTS: In terms of staining intensity, the low-intensity cadherin-11 group showed longer progression-free survival (PFS) than the high-intensity cadherin-11 group (median PFS, 12.0 months [95% CI, 11.1-12.9] vs. median PFS, 6.0 months [95% CI, 3.7-8.3]; p<0.001). The low-intensity cadherin-11 group revealed longer overall survival (OS) than the high-intensity cadherin-11 group (median OS, 20.0 months [95% CI, 11.8-16.6] vs. median OS, 15.0 months [95% CI, 11.8-18.2]; p=0.003). The staining intensity of cadherin-11 was a statistically significant factor in PFS and OS in terms of univariate and multivariate analyses (univariate analysis: p<0.001 and p=0.005; multivariate analysis: p<0.001 and p=0.005). CONCLUSION: Our clinical study demonstrates high cadherin-11 expression may be associated with poor PFS and OS for a newly diagnosed primary GBL.

Transversus abdominis plane block for lumboperitoneal shunt surgery in idiopathic normal pressure hydrocephalus: a case report.

The transversus abdominis plane (TAP) block is an ideal pain control method used in surgeries that require abdominal wall incisions through the injection of an anesthetic solution into the plane between the internal oblique muscle and transversus abdominis muscle. Herein, we report an 83-year-old man who was diagnosed with idiopathic normal pressure hydrocephalus (iNPH) and underwent lumboperitoneal shunt surgery (LPS). The TAP block was performed before LPS, and the numerical rating scale for pain was 0 at day 1 after the surgery. The patient was discharged early at day 3 after surgery despite the patient being extremely old, as he reported quick relief from the postoperative abdominal pain. The TAP block can hence be considered for use before LPS in elderly patients with iNPH.

Clinical usefulness of deep learning-based automated segmentation in intracranial hemorrhage.

BACKGROUND: Doctors with various specializations and experience order brain computed tomography (CT) to rule out intracranial hemorrhage (ICH). Advanced artificial intelligence (AI) can discriminate subtypes of ICH with high accuracy. OBJECTIVE: The purpose of this study was to investigate the clinical usefulness of AI in ICH detection for doctors across a variety of specialties and backgrounds. METHODS: A total of 5702 patients' brain CTs were used to develop a cascaded deep-learning-based automated segmentation algorithm (CDLA). A total of 38 doctors were recruited for testing and categorized into nine groups. Diagnostic time and accuracy were evaluated for doctors with and without assistance from the CDLA. RESULTS: The CDLA in the validation set for differential diagnoses among a negative finding and five subtypes of ICH revealed an AUC of 0.966 (95% CI, 0.955-0.977). Specific doctor groups, such as interns, internal medicine, pediatrics, and emergency junior residents, showed significant improvement with assistance from the CDLA (p= 0.029). However, the CDLA did not show a reduction in the mean diagnostic time. CONCLUSIONS: Even though the CDLA may not reduce diagnostic time for ICH detection, unlike our expectation, it can play a role in improving diagnostic accuracy in specific doctor groups.

Handheld mechanical cell lysis chip with ultra-sharp silicon nano-blade arrays for rapid intracellular protein extraction.

This paper presents a handheld mechanical cell lysis chip with ultra-sharp nano-blade arrays fabricated by simple and cost effective crystalline wet etching of (110) silicon. The ultra-sharp nano-blade array is simply formed by the undercutting of (110) silicon during the crystalline wet etching process. Cells can be easily disrupted by the silicon nano-blade array without the help of additional reagents or electrical sources. Based on the bench-top test of the proposed device, a handheld mechanical cell lysis chip with the nano-blade arrays is designed and fabricated for direct connection to a commercial syringe. The direct connection to a syringe provides rapid cell lysis, easy handling, and minimization of the lysate dead volume. The protein concentration in the cell lysate obtained by the proposed lysis chip is quantitatively comparable to the one prepared by a conventional chemical lysis method.

A highly accurate and consistent microfluidic viscometer for continuous blood viscosity measurement.

A high-precision microfluidic viscometer with a microfluidic channel array composed of 100 indicating channels is demonstrated in this study. The relative viscosity of the sample fluid could be measured by simply counting the number of the indicating channels occupied by the sample and the reference fluids. Using lumped parameter modeling, an analytical solution of the relative viscosity is derived. In order to evaluate the performance of the developed microfluidic viscometer, the viscosity values obtained by the microfluidic viscometer are compared with the ones obtained by a conventional viscometer. In Newtonian fluid (sodium dodecyl sulfate [SDS] solution) tests, the normalized differences in the viscosities measured by two methods are less than 2.5%. In non-Newtonian fluid (whole blood, 45% hematocrit) tests at various shear rates, the viscosities measured by two methods are evaluated by a regression analysis via power law (). The k values for both the microfluidic viscometer and the conventional viscometer are 12.953 and 13.175, respectively; the n values are 0.797 and 0.807, respectively. The normalized differences in two parameters measured by two methods are less than 2%. Thus, it could be concluded that the microfluidic viscometer developed in this study is capable of measuring viscosity of both Newtonian fluid (SDS solution) and non-Newtonian fluid (whole blood) with a relatively high accuracy in a continuous and near real-time fashion. Furthermore, the viscometer could be potentially employed in cardiopulmonary bypass procedures by continuously monitoring viscosity changes due to blood damages and hemodilution.