Exploring the Architectural Biases of the Canonical Cortical Microcircuit.

The cortex plays a crucial role in various perceptual and cognitive functions, driven by its basic unit, the canonical cortical microcircuit. Yet, we remain short of a framework that definitively explains the structure-function relationships of this fundamental neuroanatomical motif. To better understand how physical substrates of cortical circuitry facilitate their neuronal dynamics, we employ a computational approach using recurrent neural networks and representational analyses. We examine the differences manifested by the inclusion and exclusion of biologically-motivated inter-areal laminar connections on the computational roles of different neuronal populations in the microcircuit of two hierarchically-related areas, throughout learning. Our findings show that the presence of feedback connections correlates with the functional modularization of cortical populations in different layers, and provides the microcircuit with a natural inductive bias to differentiate expected and unexpected inputs at initialization. Furthermore, when testing the effects of training the microcircuit and its variants with a predictive-coding inspired strategy, we find that doing so helps better encode noisy stimuli in areas of the cortex that receive feedback, all of which combine to suggest evidence for a predictive-coding mechanism serving as an intrinsic operative logic in the cortex.

Surgical considerations and techniques using intraoperative indocyanine green angiography for ethmoidal dural arteriovenous fistula.

OBJECTIVE: This study aims to investigate the efficacy of microsurgery with intraoperative indocyanine green (ICG) angiography as a treatment approach for ethmoidal dural arteriovenous fistula (DAVF). METHODS: Between January 2010 and July 2021, our institution encountered a total of eight cases of ethmoidal DAVF. In each of these cases, microsurgical treatment was undertaken utilizing a bilateral sub-frontal interhemispheric approach, with the aid of intraoperative ICG angiography. RESULTS: ICG angiography identified bilateral venous drainage with single dominance in four cases (50%) of ethmoidal DAVF, a finding that eluded detection during preoperative transfemoral cerebral angiography (TFCA). The application of microsurgical treatment, in conjunction with intraoperative ICG angiography, resulted in consistently positive clinical outcomes for all patients, as evaluated using the Glasgow Outcome Scale (GOS) at the 6-month postoperative follow-up assessment; six patients showed GOS score of 5, while the remaining two patients attained a GOS score of 4. CONCLUSIONS: The use of intraoperative ICG angiography enabled accurate identification of both dominant and non-dominant venous drainage patterns, ensuring complete disconnection of the fistula and reducing the risk of recurrence.

Various treatment modalities for isolated intracranial middle cerebral arterial dissection with progressive ischemic symptoms: 2 case reports of endovascular stent and bypass surgery.

Isolated middle cerebral artery dissection (MCAD) is rare but increasingly recognized as a significant clinical entity, particularly in younger adults. Ischemic stroke is the most common manifestation in symptomatic cases but symptoms can vary in severity from headaches to severe neurologic deficits. Due to its rarity and unpredictable clinical course, there is no established treatment strategy for isolated MCAD. Through two case reports, we reviewed the post-operative clinical course of MCAD under different treatment modalities. Case 1 was a 21-year-old woman who presented to the emergency department with headaches and left-side hemiparesis. Isolated MCAD was diagnosed and she was successfully treated with the placement of a self-expandable stent and subsequent chemical angioplasty for post-stent vasospasm. Case 2 was a 35-year-old woman who presented to the emergency department with left-side hemiparesis and dysarthria. Isolated MCAD was diagnosed and she was successfully treated with superficial temporal artery (STA) to middle cerebral artery (MCA) anastomosis.

Safety and efficacy of nilotinib in adult patients with chronic myeloid leukemia: a post-marketing surveillance study in Korea.

Background: Nilotinib is a tyrosine kinase inhibitor approved by the Ministry of Food and Drug Safety for frontline and 2nd line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). This study aimed to confirm the safety and efficacy of nilotinib in routine clinical practice within South Korea. Methods: An open-label, multicenter, single-arm, 12-week observational post-marketing surveillance (PMS) study was conducted on 669 Korean adult patients with Ph+ CML from December 24, 2010, to December 23, 2016. The patients received nilotinib treatment in routine clinical practice settings. Safety was evaluated by all types of adverse events (AEs) during the study period, and efficacy was evaluated by the complete hematological response (CHR) and cytogenetic response. Results: During the study period, AEs occurred in 61.3% (410 patients, 973 events), adverse drug reactions (ADRs) in 40.5% (271/669 patients, 559 events), serious AEs in 4.5% (30 patients, 37 events), and serious ADRs in 0.7% (5 patients, 8 events). Furthermore, unexpected AEs occurred at a rate of 6.9% (46 patients, 55 events) and unexpected ADRs at 1.2% (8 patients, 8 events). As for the efficacy results, CHR was achieved in 89.5% (442/494 patients), and minor cytogenetic response or major cytogenetic response was achieved in 85.8% (139/162 patients). Conclusion: This PMS study shows consistent results in terms of safety and efficacy compared with previous studies. Nilotinib was well tolerated and efficacious in adult Korean patients with Ph+ CML in routine clinical practice settings.

Versatile Usage of the Modified Lateral Mass Screw as an Alternative to Cervical Pedicle Screw Fixation.

OBJECTIVE: Posterior subaxial cervical screw fixation is commonly performed using the cervical pedicle screws (CPS) and lateral mass screws (LMS); however, their compatibility is low. Modified lateral mass screws (mLMS, also called paravertebral foramen screw) fixation was introduced as a salvage technique for LMS fixation and has features of both LMS and CPS techniques. In the present study, the use of mLMS as an alternative to CPS was analyzed based on clinical results. METHODS: Seventy-eight screws (38 CPSs and 40 mLMSs) were inserted into 12 patients. The misplacement of the screws was evaluated by computed tomography (CT). The failure of instrumentation and instability were evaluated using plain radiographs. RESULTS: The total number of CPS misplacements was 3 (10.5%); however, neurologic complications were not observed. mLMSs were used in the middle segments of the fusion in 10 patients and 2 patients had mLMS fixation for single-level fusion. An additional bridging implant was not required for connecting both CPSs and mLMSs. Instability was not observed during the observation period (4-51 months). Complete fusion was seen in 10 patients. CONCLUSIONS: The alternative mLMS fixation can decrease the risk of screw misplacement compared with CPS fixation alone and achieves adequate stability leading to fusion.

Simultaneous neck coverage and branch preservation using the proximal portion of a self-expandable open-cell stent for embolization of distal internal carotid artery aneurysms: multi-center, long-term results.

PURPOSE: We report the long-term results of a modified stent-assisted coil embolization technique using the far proximal part of a self-expanding open-cell stent. The technique was used to cover the neck of the aneurysm while simultaneously preserving the branches of the distal internal carotid artery in patients with aneurysms of the posterior communicating (Pcom) and anterior choroidal arteries (AchA). METHODS: We performed a retrospective review of the prospectively maintained databases at two tertiary neurosurgical centers to identify all patients who underwent embolization of Pcom or AchA aneurysms using this technique between January 2014 and July 2019. Postoperative and follow-up clinical and radiological results for initial (n = 16) or re-do (n = 4) embolizations were analyzed. RESULTS: We identified 19 patients with 20 (16 Pcom and 4 AchA) unruptured (n = 19) or ruptured (n = 1) aneurysms. Eighteen among 20 stents (90.0%) were deployed successfully, and complete occlusions were initially attained in 18 aneurysms (90.0%). At follow-up examinations 8 to 56 months later, 6 of 14 aneurysms (42.8%) showed neck remnants. All of the branches were saved and no thromboembolic event, rupture, or sequelae were noted during or after the procedures. CONCLUSION: These results suggest that this modified stent-assisted technique is a feasible and reasonable alternative to conventional stent deployment for coil embolization of wide-necked sidewall aneurysms in the distal ICA.

Phase II study of safety and efficacy of BEB (bendamustine, etoposide, and busulfan) conditioning regimen for autologous stem cell transplantation in non-Hodgkin lymphoma.

Autologous stem cell transplant (ASCT) is an effective treatment for non-Hodgkin lymphoma (NHL). However, recent supply issues and toxicity of carmustine have necessitated a new conditioning regimen. We conducted a multicenter, phase II study of BEB (busulfan, etoposide, and bendamustine) conditioning regimen for ASCT in patients with NHL. Thirty-one patients were enrolled and underwent ASCT with the BEB conditioning regimen. The most common subtype was diffuse large B-cell lymphoma (n = 23, 74.2%). Nine patients (29.0%) had a history of relapse, and 18 patients (58.1%) received more than 2 lines of chemotherapy before ASCT. A median number of 6.05 × 106/kg CD34 cells were infused, and all patients engrafted after a median period of 11 days. Thirteen patients (41.9%) experienced neutropenic fever, and 16 patients (51.6%) had grade 3 or 4 toxicities during ASCT. No one had a documented infection, veno-occlusive disease, or treatment-related death. Three-month complete remission rate was 81.8%. Median follow-up period of 15 months showed 6 patients (19.4%) relapsed or progressed and 3 patients died. The estimated 2-year progression-free survival and overall survival rate were 73.0% and 89.8%, respectively. Our results show that BEB conditioning regimens for ASCT are feasible with tolerable toxicity in patients with NHL.

The effectiveness and safety of lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma in real-world clinical practice: a study of the Korean Multiple Myeloma Working Party (KMMWP-151 study).

Although lenalidomide plus dexamethasone (RD) is a therapeutic option for relapsed/refractory multiple myeloma (RRMM), limited real-world clinical data exist. The purpose of this study was to estimate efficacy and safety of RD in RRMM patients of the clinical practice. Data from patients at 25 university hospitals in South Korea between October 2009 and December 2016 were collected retrospectively. We report the effectiveness and safety of RD in 546 RRMM patients in routine clinical practice in South Korea. Patients (median age, 65 years) typically received median 7 cycles of RD, and 184 (33.7%) patients were treated with 10 or more cycles of RD. Patients with renal impairment (CLCr < 40 mL/min; 10.4%), comorbid conditions (≥ 2; 12.0%), and poor performance status (≥ 2; 25.1%) were included. The overall response rate was 64.2%: complete response (13.1%), very good partial response (VGPR 19.9%). With median follow-up duration of 18.6 months, median PFS and OS were 11.2 months and 25.2 months, respectively. In multivariate analysis, less than 2 comorbid conditions, normal LDH, failed one chemotherapy prior to RD, and ≥ 10 cycles of RD therapy had significantly prolonged PFS (P = 0.007, P = 0.011, P = 0.007, and P < 0.001, respectively). Adverse events were acceptable. RD is effective and safe in real-life clinical practice, including patients with comorbidities. RD is an effective and safe treatment in a real clinical setting which includes patients with comorbidities. Early and continual use of RD treatment may improve RRMM survival outcomes.

Mutation analysis in Korean patients with T-cell acute lymphoblastic leukemia.

Genomic studies have illuminated the alterations in pathways underlying T-cell acute lymphoblastic leukemia (T-ALL) pathogenesis, but detailed mutation data by next-generation sequencing have not been reported in Korean patients. We aimed to investigate mutation frequency, spectrum, and pattern in the Korean patients with T-ALL. We designed a multigene panel targeting 101 genes and validated it using 10 reference materials. The mutation analysis was done in a total of 10 patients with T-ALL. Clinical data and laboratory tests including immunophenotyping, cytogenetics, and molecular genetic tests were also investigated. All of the 10 patients harbored at least one mutation (range 1-6 per patient). A total of 34 clinically significant mutations including 15 novel mutations were identified in 23 genes. The median of variant allelic frequencies (VAFs) and blasts were counted upto 33% (range 5-91%) and 79% (range 38-90%), respectively. Recurrent mutations were involved in epigenetic regulators (60%), NOTCH1 signaling (40%), PI3K-AKT (40%), JAK-STAT (30%), and transcription factors (30%). We found that both NOTCH signaling and JAK-STAT signaling were positively associated with epigenetic regulators, while showed mutually exclusive patterns with PI3K-AKT pathway. This study showed that the frequency of mutations in epigenetic regulators in Korean patients was significantly higher than expected. Distribution of VAF as well as mutation spectrum is considerably heterogeneous in Korean patients with T-ALL. Although from a limited number of patients, this study provides the first detailed mutational portrait of T-ALL of Korean patients, and gives additional insight into molecular pathogenesis of the disease.

Dose Adjustment Helps Obtain Better Outcomes in Multiple Myeloma Patients with Bortezomib, Melphalan, and Prednisolone (VMP) Treatment

Objective: Multiple myeloma (MM) has a better survival outcome because of the development of drugs. However, equivalent outcomes cannot be expected from the same drug. Therefore, how the treatment schedule is managed is important. We analyzed VMP (bortezomib, melphalan, and prednisolone) data to determine an effective treatment strategy. Materials and Methods: We collected the data of 59 patients who were newly diagnosed with MM from January 2012 to April 2017 using electronic medical records. We analyzed baseline characteristics, responses, dose reductions, and survival. Results: The overall response rate was 86.5% [complete response (CR): 32.2%, very good partial response (VGPR): 37.3%]. The median progression-free survival was 33.6 months and the 5-year overall survival rate was 70%. There were significant better progression-free survival outcomes between CR and non-CR for each of the 4 cycles. Of the four patients who achieved CR after the first cycle, none have had disease progression as of yet. We divided patients into two groups according to the median dose (52.1 mg/m2) and we found no differences between the high-dose and low-dose groups. About 78% of patients completed 9-cycle schedules and 84% patients experienced dose reduction, mostly for reasons of non-hematologic toxicities. Conclusion: Active dose reduction helped to continue treatment and it increased the opportunity to be exposed to drugs. In the end, it resulted in improved outcome.

Pralatrexate in patients with recurrent or refractory peripheral T-cell lymphomas: a multicenter retrospective analysis.

Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin's lymphomas with poor clinical outcomes. Pralatrexate showed efficacy and safety in recurrent or refractory PTCLs. The purpose or this study was to investigate the efficacy and safety of pralatrexate in relapsed or refractory PTCLs in real-world practice. This was an observational, multicenter, retrospective analysis. Between December 2012 and December 2016, a total of 38 patients with relapsed or refractory PTCLs were treated with pralatrexate at 10 tertiary hospitals in Korea. Patients received an intravenous infusion of pralatrexate at a dose of 30 mg/m2/week for 6 weeks on a 7-week schedule. Modified dosing and/or scheduling was allowed according to institutional protocols. Median patient age was 58 years (range, 29-80 years) and the most common subtype was peripheral T-cell lymphoma, not otherwise specified (n = 23, 60.5%). The median dosage of pralatrexate per administration was 25.6 mg/m2/wk (range, 15.0-33.0 mg/m2/wk). In intention-to-treat analysis, 3 patients (7.9%) showed a complete response and 5 patients (13.2%) showed a partial response, resulting in an overall response rate (ORR) of 21.1%. The median duration of response was 7.6 months (range, 1.6-24.3 months). The median progression-free survival (PFS) was 1.8 months (95% confidence interval [CI], 1.7-1.8 months) and the median overall survival was 7.7 months (95% CI, 4.4-9.0 months). The most common grade 3/4 adverse events were thrombocytopenia (n = 13, 34.2%), neutropenia (n = 7, 23.7%), and anemia (n = 7, 18.4%). Our study showed relatively lower ORR and shorter PFS in patients with recurrent or refractory PTCLs treated with pralatrexate in real-world practice. The toxicity profile was acceptable and manageable. We also observed significantly lower dose intensity of pralatrexate in real-world practice.

Diagnosis of Cerebral Aneurysm Via Magnetic Resonance Angiography Screening: Emphasis on Legal Responsibility Increases False Positive Rate.

PURPOSE: False positive diagnoses of cerebral aneurysm via magnetic resonance angiography (MRA) screening may increase unnecessary cerebral catheter angiography. The purpose of this study was to investigate the effects of medical liability on medical decision-making during radiologic interpretation. MATERIALS AND METHODS: We included 56 consecutive patients who were referred with suspected aneurysm based on MRA or computed tomography angiography (CTA) and showed no aneurysm on subsequent digital subtraction angiography (DSA). MRA and CTA were reviewed twice by two neuroradiology fellows who were blind as to whether the suspected lesions were true aneurysms or not. The second review was repeated after proposing that their decision was subject to legal liability and they would be responsible for medico-legal problems related to their diagnoses. Diagnostic differences based on each review were analyzed, focusing on changes in false positive diagnosis rates. RESULTS: A total of 63 suspected aneurysmal lesions detected via MRA or CTA were found to be negative based on DSA. At first review, 32 lesions were diagnosed as true aneurysms by observer 1 and 27 by observer 2, corresponding to false positive rates of 51% and 43% respectively. At the second review, 39 lesions (62%) were diagnosed by observer 1, and 30 (48%) by observer 2. Thus, there was an overall increase in false positive aneurysm diagnosis of 11% for observer 1 and 5% for observer 2, after emphasizing their responsibilities in the context of medical litigation. CONCLUSION: Concerns about medical liability could result in increased false positive diagnoses of cerebral aneurysms via MRA screening. Whether repeated follow-up of the suspected lesion or catheter angiographic confirmation is better with regard to long-term patient outcomes requires further study.

The association between substance P and white matter integrity in medication-naive patients with major depressive disorder.

Substance P (SP) has been implicated in major depressive disorder (MDD), with SP antagonists being studied as potential antidepressants. Although impaired neural plasticity is considered a key mechanism in MDD pathophysiology, the association between SP and brain structural changes in depression has not been investigated. We investigated the correlations between SP levels and white matter (WM) integrity in 42 medication-naive patients with MDD and 57 healthy controls (HCs). Plasma levels of SP were determined, and diffusion tensor imaging (DTI) was performed to investigate microstructural changes in WM tracts. In patients, negative correlations between SP levels and fractional anisotropy (FA) values of the forceps minor of the corpus callosum, and positive correlations between SP levels and radial diffusivity (RD) and mean diffusivity (MD) values of the right corticospinal tract (CST) were observed, with no significant correlations in HCs. Linear regression analyses showed SP levels to significantly predict FA values of the forceps minor, and RD and MD values of the right CST in patients, but not in HCs. We consider our findings to contribute to the neurobiological evidence on the association between SP and brain structural changes in depression, which may be related with the pathophysiology and treatment of MDD.

Therapeutic decision-making in elderly patients with acute myeloid leukemia: conventional intensive chemotherapy versus hypomethylating agent therapy.

Standards of care for elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy remain undefined. We aimed to compare outcomes of hypomethylating agent (HMA) therapy and intensive chemotherapy (IC) in elderly AML patients and identify the subgroup of patients who are eligible for HMA therapy. We reviewed data on the outcomes of 86 AML patients aged ≥ 65 years, who had undergone treatment between 2010 and 2015. These treatments included IC (25 patients, 29.1%) or therapy using HMA including azacitidine or decitabine (61 patients, 70.9%). The overall response rates were 32 and 19.7%, respectively. Median overall survival (OS) (8 vs. 8 months) and progression-free survival (PFS) (6 vs. 7 months) durations were similar in the two groups. Patients in the HMA group with less than 10% peripheral blood (PB) blasts achieved significantly better OS duration than patients in the IC group (P = 0.043). Patients in the IC group with PB blasts and bone marrow blast of ≥ 10 and ≥ 50%, respectively, achieved better PFS durations than the corresponding patients in the HMA group (P = 0.038). Multivariate analysis identified the hematologic improvement-platelet (HI-P) as an independent prognostic factor for survival in the HMA group (P = 0.005). Our results showed that HMA therapy and IC were associated with similar survival duration in elderly AML patients. This study was noteworthy because it assessed prognostic factors that would help to select elderly patients who could expect actual benefits from undergoing the different therapeutic options available, especially HMA therapy.

Crystal structure of LysK, an enzyme catalyzing the last step of lysine biosynthesis in Thermus thermophilus, in complex with lysine: Insight into the mechanism for recognition of the amino-group carrier protein, LysW.

LysK is an M20 peptidase family enzyme that hydrolyzes the isopeptide bond between the carrier protein LysW and lysine in order to release lysine, which is the last step of lysine biosynthesis in Thermus thermophilus. In the present study, we determined the crystal structure of LysK in complex with lysine at a resolution of 2.4 Å. The α-amino group of the bound lysine was oriented toward the catalytic center, which was composed of the residues coordinating divalent metal ions for the hydrolysis of the isopeptide bond. An 11 Å-long path was observed from the active site binding lysine to the protein surface, which may be responsible for recognizing the C-terminal extension domain of LysW with the conserved EDWGE sequence. A positively-charged surface region was detected around the exit of the path, similar to other lysine biosynthetic enzymes using LysW as the carrier protein. Mutational studies of the surface residues provided a plausible model for the electrostatic interaction with LysW.

Fosfomycin Biosynthesis via Transient Cytidylylation of 2-Hydroxyethylphosphonate by the Bifunctional Fom1 Enzyme.

Fosfomycin is a wide-spectrum phosphonate antibiotic that is used clinically to treat cystitis, tympanitis, etc. Its biosynthesis starts with the formation of a carbon-phosphorus bond catalyzed by the phosphoenolpyruvate phosphomutase Fom1. We identified an additional cytidylyltransferase (CyTase) domain at the Fom1 N-terminus in addition to the phosphoenolpyruvate phosphomutase domain at the Fom1 C-terminus. Here, we demonstrate that Fom1 is bifunctional and that the Fom1 CyTase domain catalyzes the cytidylylation of the 2-hydroxyethylphosphonate (HEP) intermediate to produce cytidylyl-HEP. On the basis of this new function of Fom1, we propose a revised fosfomycin biosynthetic pathway that involves the transient CMP-conjugated intermediate. The identification of a biosynthetic mechanism via such transient cytidylylation of a biosynthetic intermediate fundamentally advances the understanding of phosphonate biosynthesis in nature. The crystal structure of the cytidylyl-HEP-bound CyTase domain provides a basis for the substrate specificity and reveals unique catalytic elements not found in other members of the CyTase family.

Bench-top Comparison of Physical Properties of 4 Commercially-Available Self-Expanding Intracranial Stents.

PURPOSE: To better understand the performance of four commercially available neurovascular stents in intracranial aneurysm embolization, the stents were compared in terms of their basic morphological and mechanical properties. MATERIALS AND METHODS: Four different types of stents that are currently being used for cerebral aneurysm embolization were prepared (two stents per type). Two were laser-cut stents (Neuroform and Enterprise) and two were braided from a single nitinol wire (LEO and LVIS stents). All were subjected to quantitative measurements of stent size, pore density, metal coverage, the force needed to load, push, and deploy the stent, radial force on deployment, surface roughness, and corrosion resistance. RESULTS: Compared to their nominal diameters, all stents had greater diameters after deployment. The length generally decreased after deployment. This was particularly marked in the braided stents. The braided stents also had higher pore densities than the laser-cut stents. Metal coverage was highest in the LEO stent (14%) and lowest in the Enterprise stent (5%). The LIVS stent had the highest microcatheter loading force (81.5 gf). The LEO stent had the highest passage force (55.0 gf) and deployment force (78.9 gf). The LVIS and LEO stents had the highest perpendicular (37.1 gf) and circumferential (178.4 gf) radial forces, respectively. The Enterprise stent had the roughest stent wire, followed by the LVIS, LEO, and Neuroform stents. CONCLUSION: The four neurovascular stent types differed in terms of morphological and physical characteristics. An understanding of this diversity may help to decide which stent is most suitable for specific clinical situations.

Clinical features and treatment outcome of Epstein-Barr virus-positive nodal T-cell lymphoma.

The classification of mature NK-/T-cell lymphoma mainly originating from the T-cell lineage with predominantly nodal involvement and Epstein-Barr virus (EBV) positivity in a majority of tumor cells is unresolved. We analyzed the clinical features and treatment outcomes of such patients. Five patients with EBV-positive nodal T-cell lymphoma were surveyed during follow-up period. The median age was 53 years (range 33-88 years), and all patients showed nodal involvement. The patients mostly presented advanced clinical features, such as stage III or IV disease, elevated lactate dehydrogenase, and hemophagocytosis. Four patients received cyclophosphamide-containing chemotherapy at the time of diagnosis. However, three patients (75 %) showed disease progression during the early cycles of initial treatment. The median overall survival was 1.5 months (95 % CI 0.0-3.4 months). Patients with EBV-positive nodal T-cell lymphoma mainly show lymph node involvement, but also show aggressive clinical features and poor treatment outcomes, such as aggressive NK-cell leukemia. Therefore, we should consider EBV-positive nodal T-cell lymphoma to be a unique disease entity distinct from peripheral T-cell lymphoma not otherwise specified.