Delayed Cerebral Toxoplasmosis in a Kidney Transplant Patient: a Case Report.

Cerebral toxoplasmosis is often life-threatening in an immunocompromised patient due to delayed diagnosis and treatment. Several differential diagnoses could be possible only with preoperative brain images of cerebral toxoplasmosis which show multiple rim-enhancing lesions. Due to the rarity of cerebral toxoplasmosis cases in Korea, the diagnosis and treatment are often delayed. This paper concerns a male patient whose cerebral toxoplasmosis was activated 21 years post kidney transplantation. Brain open biopsy was decided to make an exact diagnosis. Cerebral toxoplasmosis was confirmed by immunohistochemistry and PCR analyses of the tissue samples. Although cerebral toxoplasmosis was under control with medication, the patient did not recover clinically and died due to sepsis and recurrent gastrointestinal bleeding.

Crystal structure of CD38 in complex with daratumumab, a first-in-class anti-CD38 antibody drug for treating multiple myeloma.

Multiple myeloma is a blood cancer characterized by the plasma cell malignancy in the bone marrow, resulting in the destruction of bone tissue. Recently, the US FDA approved two antibody drugs for the treatment of multiple myeloma, daratumumab and isatuximab, targeting CD38, a type II transmembrane glycoprotein highly expressed in plasma cells and multiple myeloma cells. Here, we report the crystal structure of CD38 in complex with the Fab fragment of daratumumab, providing its exact epitope on CD38 and the structural insights into the mechanism of action of the antibody drug. Daratumumab binds to a specific discontinuous region on CD38 that includes residues located opposite to the active site of CD38. All the six complementarity determining regions of daratumumab are involved in the CD38 interaction. The epitopes of daratumumab and isatuximab do not overlap at all and their bindings to CD38 induce different structural changes within the CD38 protein. This structural study can facilitate the design of improved biologics or effective combination therapies for the treatment of multiple myeloma.

High-resolution structure of the vWF A1 domain in complex with caplacizumab, the first nanobody-based medicine for treating acquired TTP.

von Willebrand factor (vWF) is a huge oligomeric glycoprotein involved in blood homeostasis. However, this protein is also implicated in acquired thrombotic thrombocytopenic purpura (TTP). The blocking of its binding with platelets has been recognized as an attractive therapeutic strategy for treating acquired TTP. Caplacizumab, a bivalent single-domain antibody (VHH), is the first FDA-approved nanobody drug against vWF for the treatment of acquired TTP. Here, we describe the crystal structure of the A1 domain of vWF in complex with the caplacizumab nanobody at the resolution of 1.60 Å. This structure elucidates the precise epitope and binding mode of caplacizumab. Unexpectedly, caplacizumab binds to the bottom face of the vWF A1 domain and does not create any steric clash with platelet-receptor glycoprotein Ib (GPIb) bound to vWF. However, its binding can stabilize the different conformation within the N-terminus and α1ß2 loop from the GPIb bound structure, suggesting that the mechanisms of caplacizumab would not be the direct competition of GPIb binding to vWF A1 domain but the conformational arrestment of vWF in an inappropriate state to platelet adhesion. This high-resolution structure would provide helpful information for the design of improved anti-vWF therapeutics for the treatment of acquired TTP.

Crystal structure of PD-1 in complex with an antibody-drug tislelizumab used in tumor immune checkpoint therapy.

Blocking of the interaction between Programmed cell death 1 (PD-1) and its ligand PD-L1 by monoclonal antibodies has elicited unprecedented therapeutic benefits and achieved a major breakthrough in immunotherapy of multiple types of tumors. Here, we determined the crystal structure of PD-1 in complex with the Fab fragment of tislelizumab. This monoclonal antibody was approved in December 2019 by the China National Medical Product Administration for Hodgkin's lymphoma and is under multiple clinical trials in China and the US. While the three complementarity determining regions (CDRs) in the light chain are involved in the target interaction, only CDR3 within the heavy chain interacts with PD-1. Tislelizumab binds the front ß-sheet of PD-1 in a very similar way as PD-L1 binds to PD-1, thereby blocking the PD-1/PD-L1 interaction with a higher affinity. A comparative analysis of PD-1 interactions with therapeutic antibodies targeting PD-1 provides a better understanding of the blockade mechanism of PD-1/PD-L1 interaction in addition to useful information for the improvement of therapeutic antibodies capable of diminishing checkpoint signaling for cancer immunotherapy.

Increase in the nuclear localization of PTEN by the Toxoplasma GRA16 protein and subsequent induction of p53-dependent apoptosis and anticancer effect.

This study investigated the efficacy of Toxoplasma GRA16, which binds to herpes virus-associated ubiquitin-specific protease (HAUSP), in anticancer treatment, and whether the expression of GRA16 in genetically modified hepatocellular carcinoma (HCC) cells (GRA16-p53-wild HepG2 and GRA16-p53-null Hep3B) regulates PTEN because alterations in phosphatase and tensin homologue (PTEN) and p53 are vital in liver carcinogenesis and the abnormal p53 gene appears in HCC. For this purpose, we established the GRA16 cell lines using the pBABE retrovirus system, assessed the detailed mechanism of PTEN regulation in vitro and established the anticancer effect in xenograft mice. Our study showed that cell proliferation, antiapoptotic factors, p-AKT/AKT ratio, cell migration and invasive activity were decreased in GRA16-stable HepG2 cells. Conversely, the apoptotic factors PTEN and p53 and apoptotic cells were elevated in GRA16-stable HepG2 cells but not in Hep3B cells. The change in MDM2 was inconspicuous in both HepG2 and Hep3B; however, the PTEN level was remarkably elevated in HepG2 but not in Hep3B. HAUSP-bound GRA16 preferentially increased p53 stabilization by the nuclear localization of PTEN rather than MDM2-dependent mechanisms. These molecular changes appeared to correlate with the decreased tumour mass in GRA16-stable-HepG2 cell-xenograft nude mice. This study establishes that GRA16 is a HAUSP inhibitor that targets the nuclear localization of PTEN and induces the anticancer effect in a p53-dependent manner. The efficacy of GRA16 could be newly highlighted in HCC treatment in a p53-dependent manner.

Molecular Interactions of Antibody Drugs Targeting PD-1, PD-L1, and CTLA-4 in Immuno-Oncology.

Cancer cells can evade immune surveillance through the molecular interactions of immune checkpoint proteins, including programmed death 1 (PD-1), PD-L1, and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Since 2011, the FDA-approved antibody drugs ipilimumab (Yervoy®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), cemiplimab (Libtayo®), atezolizumab (Tecentriq®), durvalumab (Imfinzi®), and avelumab (Bavencio®), which block the immune checkpoint proteins, have brought about a significant breakthrough in the treatment of a wide range of cancers, as they can induce durable therapeutic responses. In recent years, crystal structures of the antibodies against PD-1, PD-L1, and CTLA-4 have been reported. In this review, we describe the latest structural studies of these monoclonal antibodies and their interactions with the immune checkpoint proteins. A comprehensive analysis of the interactions of these immune checkpoint blockers can provide a better understanding of their therapeutic mechanisms of action. The accumulation of these structural studies would provide a basis that is essential for the rational design of next-generation therapies in immuno-oncology.

Genomic analysis of synchronous intracranial meningiomas with different histological grades.

Although meningioma is the most common primary tumor of the central nervous system, the mechanism of progression from benign to atypical or anaplastic grade remains elusive. The present case reports the genomic evaluation of two synchronous meningiomas with different histological grades (benign and atypical) in the same patient. Under the assumption that the atypical tumor may have progressed from the benign tumor, the clonal origin of the lesions was investigated to identify genomic events responsible for the oncogenic process of evolution to higher grades in meningioma. A 59 year-old female patient was diagnosed with two synchronous meningiomas with different histological grades, benign and atypical. Whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analysis of both tumors were done. WES analysis showed that each meningioma harbored distinct mutation profiles, and RNA-seq analysis revealed distinct gene expression profiles between the two tumors. The only apparent common genetic abnormality found in both tumors was the loss of heterozygosity of chromosome 22, raising the possibility that this event is the initial step in tumor formation, after which distinct subsequent mutations lead to the evolvement of two separate tumors of different grades. The result provides additional evidence on previous reports suggesting separate, independent mechanism of progression into higher grades in meningioma.

Structural Biology of the TNFα Antagonists Used in the Treatment of Rheumatoid Arthritis.

The binding of the tumor necrosis factor α (TNFα) to its cognate receptor initiates many immune and inflammatory processes. The drugs, etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab-pegol (Cimzia®), and golimumab (Simponi®), are anti-TNFα agents. These drugs block TNFα from interacting with its receptors and have enabled the development of breakthrough therapies for the treatment of several autoimmune inflammatory diseases, including rheumatoid arthritis, Crohn's disease, and psoriatic arthritis. In this review, we describe the latest works on the structural characterization of TNFα-TNFα antagonist interactions related to their therapeutic efficacy at the atomic level. A comprehensive comparison of the interactions of the TNFα blockers would provide a better understanding of the molecular mechanisms by which they neutralize TNFα. In addition, an enhanced understanding of the higher order complex structures and quinary structures of the TNFα antagonists can support the development of better biologics with the improved pharmacokinetic properties. Accumulation of these structural studies can provide a basis for the improvement of therapeutic agents against TNFα for the treatment of rheumatoid arthritis and other autoimmune inflammatory diseases in which TNFα plays an important role in pathogenesis.

Effects of Antioxidants in Reducing Accumulation of Fat in Hepatocyte.

The progress of the hepatic steatosis (HS), a clinicopathological status, is influenced by cellular oxidative stress, lipogenesis, fatty acid (FA) oxidation, and inflammatory responses. Because antioxidants are gaining attention as potent preventive agents for HS, we aimed to investigate anti-lipogenic effects of the antioxidants vitamin C (VC), N-acetylcysteine (NAC), and astaxanthin (ATX) using hepatocytes. For this, we established an in vitro model using 1 mM oleic acid (OA) and human liver hepatocellular carcinoma (HepG2) cells; 10 µM antioxidants were evaluated for their ability to reduce fat accumulation in hepatocytes. Our results showed that all three antioxidants were effective to reduce fat accumulation for the molecular targets such as reduction in lipid droplets, triglyceride (TG) concentration, reactive oxygen species (ROS) production, and cell apoptosis, as well as in gene expressions of endoplasmic reticulum (ER) stress-related effectors, lipogenesis, and inflammatory cytokines. There were simultaneous increases in diphenyl-1-picrylhydrazyl (DPPH) radical scavenging effect, cell survival, AMPK phosphorylation, NRF2-related gene expression for cellular defense, and FA ß-oxidation. However, among these, ATX more effectively inhibited ER stress and lipogenesis at the intracellular level than VC or NAC. Consequently, ATX was also more effective in inhibiting cell death, lipotoxicity, and inflammation. Our result emphasizes that ATX achieved greater lipotoxicity reduction than VC and NAC.

Cutaneous anaplastic large-cell lymphoma (ALCL): A comparative clinical feature and survival outcome analysis of 52 cases according to primary tumor site.

BACKGROUND: Cutaneous anaplastic large-cell lymphoma (ALCL) is primary extranodal or secondary to nodal disease. OBJECTIVE: We sought to analyze clinical features and survival outcomes by primary tumor site in patients with cutaneous ALCL. METHODS: Clinical features, survival outcomes, and prognostic factors of 52 patients with primary or secondary cutaneous ALCL to primary nodal disease were retrospectively evaluated using medical records. RESULTS: Although skin lesion characteristics did not significantly differ between groups, the head and neck location was more common in primary cutaneous ALCL, whereas cutaneous lesion extent was greater in secondary cutaneous ALCL. Skin lesion extent in primary cutaneous ALCL was indicative of extracutaneous dissemination development and skin lesion relapse. Neither anaplastic lymphoma kinase expression nor clinical stage affected skin lesion characteristics in secondary cutaneous ALCL. Patients with primary rather than secondary cutaneous ALCL demonstrated better survival outcomes. The skin lesion extent and location on the leg were associated with the tendency toward a poorer prognosis in primary cutaneous ALCL. The secondary cutaneous ALCL prognosis was not influenced by skin lesion characteristics. LIMITATIONS: This was a retrospective study in a single institution. CONCLUSION: Survival outcomes and prognostic factors in cutaneous ALCL differed by primary tumor site.

Relative Frequency, Clinical Features, and Survival Outcomes of 395 Patients with Cutaneous Lymphoma in Korea: A Subgroup Analysis per 10-year Period.

Long-term changes in the relative frequency of cutaneous lymphoma (CL) have not been investigated in Asian populations. The aim of this study was to investigate the relative frequency, clinical characteristics, and survival outcomes of CL in Korean patients, and to evaluate the changes in relative frequency of CL over a 20-year period. The present retrospective cohort study included 395 patients, of whom 289 had primary CL and 106 secondary CL, seen at a tertiary referral hospital in Seoul, Korea. Primary CL included T-/NK-cell linage lymphoma (CTCL, 85.1%) and B-cell lineage lymphoma (CBCL, 14.9%). The relative frequency of CBCL increased over time, as shown by a decrease in the CTCL/CBCL ratio from 10.3 in 1994 to 2003 to 4.5 in 2004 to 2013. CTCL was more commonly associated with multiple and extensive skin lesions than CBCL. Extranodal NK/T-cell lymphoma and subcutaneous panniculitis-like T-cell lymphoma were commonly associated with extensive skin lesions. The 5-year overall survival rate for all patients with primary CL was 81%.

A prospective, split-face, double-blinded, randomized study of the efficacy and safety of a fractional 1064-nm Q-switched Nd:YAG laser for photoaging-associated mottled pigmentation in Asian skin.

BACKGROUND: Laser toning using low-fluence 1064-nm Q-switched neodymium-doped yttrium aluminum laser (QSNY) has gained popularity in the treatment of photoaging-associated mottled pigmentation (PMP). However, hypopigmentation or lack of efficacy has been reported depending on the fluences used. OBJECTIVE: To compare a novel fractional 1064-nm QSNY with conventional 1064-nm QSNY for the treatment of photoaging-associated mottled pigmentary lesions except epidermal lesions of lentigines and freckles through a randomized, split-face, double-blind study. MATERIALS AND METHODS: Thirteen Asian women were treated every week for 6 weeks with fractional 1064-nm QSNY on one side of the face and conventional 1064-nm QSNY on the other side. We evaluated the pigmentation area and severity index (PSI), melanin index, erythema index, and the patient's global assessment of improvement. RESULTS: At three months post-treatment, the PSI score improved compared with baseline, by 14.48% on the conventional 1064-nm QSNY side and 21.81% on the fractional 1064-nm QSNY side. Both groups showed improvements in the melanin index. CONCLUSION: Both fractional 1064-nm QSNY and strictly low-fluence conventional 1064-nm QSNY are moderately effective against PMP and other photoaging signs. Fractional laser toning shows better subjective outcomes than conventional toning.

A prospective, split-face, randomized study of the efficacy and safety of a novel fractionated intense pulsed light treatment for melasma in Asians.

BACKGROUND: Intense pulsed light (IPL) has been reported to effectively treat melasma in previous studies, but an aggravation of pigmentation was noted. Fractionated IPL is a novel technique in which microsecond-domain fractionated pulses are delivered to the target area. OBJECTIVE: To compare the safety and efficacy of low-fluency, frequently scheduled fractionated IPL and conventional IPL for melasma treatment. MATERIALS AND METHODS: This was a 14-week, split-face study in which 30 Asian women were treated with weekly fractionated IPL on one side of the face and biweekly conventional IPL on the other side. RESULTS: The non-inferiority of a weekly fractionated IPL regimen to a biweekly conventional IPL regimen was verified by a lower margin of the 95% confidence interval for the difference in the Melasma Area and Severity Index (MASI) change from baseline of 2.61 for each side. This value was greater than the previously determined non-inferiority margin of -2.68 (P < 0.025). On the fractionated IPL side, the modified MASI score decreased continuously, but in the conventional IPL group, the MASI score rebounded during the treatment course. CONCLUSION: Fractionated IPL shows moderate efficacy as a melasma treatment and is therefore a good alternative to conventional IPL as there is no indication of melasma exacerbation. Fractionated IPL can also be used as a maintenance treatment for melasma.

Dopamine and Cu+/2+ can induce oligomerization of α-synuclein in the absence of oxygen: Two types of oligomerization mechanisms for α-synuclein and related cell toxicity studies.

α-Synuclein oligomers can induce neurotoxicity and are implicated in Parkinson's disease etiology and disease progression. Many studies have reported α-synuclein oligomerization by dopamine (DA) and transition metal ions, but few studies provide insight into joint influences of DA and Cu2+ . In this study, DA and Cu2+ were coadministered aerobically to measure α-synuclein oligomerization under these conditions. In the presence of oxygen, DA induced α-synuclein oligomerization in a dose-dependent manner. Cu+/2+ did not effect oligomerization in such a manner in the presence of DA. By electrophoresis, Cu2+ was found easily to induce oligomerization with DA. This implies that oligomerization invoked by DA is reversible in the presence of Cu2+, which appears to be mediated by noncovalent bond interactions. In the absence of oxygen, DA induced less oligomerization of α-synuclein, whereas DA/Cu2+ induced aerobic-level amounts of oligomers, suggesting that DA/Cu2+ induces oligomerization independent of oxygen concentration. Radical species were detected through electron paramagnetic resonance (EPR) spectroscopic analysis arising from coincubation of DA/Cu2+ with α-synuclein. Redox reactions induced by DA/Cu2+ were observed in multimer regions of α-synuclein oligomers through NBT assay. Cellular toxicity results confirm that, for normal and hypoxic conditions, copper or DA/Cu2+ can induce cell death, which may arise from copper redox chemistry. From these results, we propose that DA and DA/Cu2+ induce different mechanisms of α-synuclein oligomerization, cross-linking with noncovalent (or reversible covalent) bonding vs. likely radical-mediated covalent modification.

Plasminogen activator inhibitor-1 promotes synaptogenesis and protects against aß(1-42)-induced neurotoxicity in primary cultured hippocampal neurons.

Plasminogen activator inhibitor-1 (PAI-1) is a soluble factor that is released from astrocytes, the most abundant type of glial cell in the brain. PAI-1 was initially identified as inhibiting two types of plasminogen activators, that is, tissue-type plasminogen and urokinase activators that are known to lead to the proteolytic degradation of the extracellular matrix. Recently, PAI-1 was reported to mediate the neuroprotective activity of transforming growth factor-ß1 against N-methyl-D-aspartate receptor-mediated excitotoxicity and to be involved in angiogenesis following ischemic stroke, independently of the effects via the inhibition of tissue-type plasminogen and urokinase-type plasminogen activators. In this study, we examined whether PAI-1 influences synaptogenesis and neurotoxicity induced by amyloid beta peptide(1-42) (Aß(1-42)) in rat primary hippocampal neurons. Using immunostaining, treatment with PAI-1 for 24 h was found to significantly upregulate synaptophysin, postsynaptic density-95, and the polysialylated form of neural cell adhesion molecule, compared to treatment with vehicle alone. In addition, PAI-1 has neuroprotective effects against Aß(1-42)-induced cytotoxicity in rat primary cultured hippocampal neurons. Taken together, our results suggest that PAI-1 has therapeutic potential in Alzheimer's disease by promoting synaptogenesis and by demonstrating neuroprotective effects against Aß(1-42)-oligomer-induced neurotoxicity in rat primary cultured hippocampal neurons.

Location of Ulnar Nerve Branches to the Flexor Carpi Ulnaris during Surgery for Cubital Tunnel Syndrome.

OBJECTIVE: Cubital tunnel syndrome, the most common ulnar nerve entrapment neuropathy, is usually managed by simple decompression or anterior transposition. One of the concerns in transposition is damage to the nerve branches around the elbow. In this study, the location of ulnar nerve branches to the flexor carpi ulnaris (FCU) was assessed during operations for cubital tunnel syndrome to provide information to reduce operation-related complications. METHODS: A personal series (HJY) of cases operated for cubital tunnel syndrome was reviewed. Cases managed by transposition and location of branches to the FCU were selected for analysis. The function of the branches was confirmed by intraoperative nerve stimulation and the location of the branches was assessed by the distance from the center of medial epicondyle. RESULTS: There was a total of 61 cases of cubital tunnel syndrome, among which 31 were treated by transposition. Twenty-one cases with information on the location of branches were analyzed. The average number of ulnar nerve branches around the elbow was 1.8 (0 to 3), only one case showed no branches. Most of the cases had one branch to the medial head, and one other to the lateral head of the FCU. There were two cases having branches without FCU responses (one branch in one case, three branches in another). The location of the branches to the medial head was 16.3±8.6 mm distal to the medial epicondyle (16 branches; range, 0 to 35 mm), to the lateral head was 19.5±9.5 mm distal to the medial epicondyle (19 branches; range, -5 to 30 mm). Branches without FCU responses were found from 20 mm proximal to the medial condyle to 15 mm distal to the medial epicondyle (five branches). Most of the branches to the medial head were 15 to 20 mm (50% of cases), and most to the lateral head were 15 to 25 mm (58% of cases). There were no cases of discernable weakness of the FCU after operation. CONCLUSION: In most cases of cubital tunnel syndrome, there are ulnar nerve branches around the elbow. Although there might be some cases with branches without FCU responses, most branches are to the FCU, and are to be saved. The operator should be watchful for branches about 15 to 25 mm distal to the medial epicondyle, where most branches come out.

Novel Postoperative Serum Biomarkers in Atypical Meningiomas: A Multicenter Study.

BACKGROUND: There has been no known serum biomarker to predict the prognosis of atypical meningioma. OBJECTIVE: To investigate the prognostic impact of serum biomarkers in patients newly diagnosed with resected intracranial atypical meningiomas. METHODS: This study enrolled 523 patients with atypical meningioma who underwent surgical resection between 1998 and 2018 from 5 Asian institutions. Serum laboratory data within 1 week after surgery were obtained for analysis. Optimal cutoffs were calculated for each serum marker using the maxstat package of R. RESULTS: Of 523 patients, 19.5% underwent subtotal resection and 29.8% were treated with adjuvant radiation therapy (ART). Among the 523 patients, 454 were included in the multivariate analysis for the progression/recurrence (P/R) rate excluding patients with incomplete histopathologic or laboratory data. On multivariate analysis, tumor size >5 cm, subtotal resection, and postoperative aspartate aminotransferase/alanine transaminase (De Ritis) ratio >2 were associated with higher P/R rates, whereas ART and postoperative platelet count >137 × 10 3 /µL were associated with lower P/R rates. In the subgroup of patients treated with ART, tumor size >5 cm and postoperative neutrophil-to-lymphocyte ratio >21 were associated with higher P/R rates. By contrast, postoperative De Ritis ratio >2 remained an adverse prognosticator in patients not treated with ART. CONCLUSION: Postoperative De Ritis ratio, platelet count, and neutrophil-to-lymphocyte ratio were revealed as a novel serum prognosticator in newly diagnosed atypical meningiomas. Additional studies are warranted to validate its clinical significance and biological background.

Telemedicine Protocols for the Management of Patients with Acute Spontaneous Intracerebral Hemorrhage in Rural and Medically Underserved Areas in Gangwon State: Recommendations for Doctors with Less Expertise at Local Emergency Rooms.

Previously, we reported the concept of a cloud-based telemedicine platform for patients with intracerebral hemorrhage (ICH) at local emergency rooms in rural and medically underserved areas in Gangwon state by combining artificial intelligence and remote consultation with a neurosurgeon. Developing a telemedicine ICH treatment protocol exclusively for doctors with less ICH expertise working in emergency rooms should be part of establishing this system. Difficulties arise in providing appropriate early treatment for ICH in rural and underserved areas before the patient is transferred to a nearby hub hospital with stroke specialists. This has been an unmet medical need for decade. The available reporting ICH guidelines are realistically possible in university hospitals with a well-equipped infrastructure. However, it is very difficult for doctors inexperienced with ICH treatment to appropriately select and deliver ICH treatment based on the guidelines. To address these issues, we developed an ICH telemedicine protocol. Neurosurgeons from four university hospitals in Gangwon state first wrote the guidelines, and professors with extensive ICH expertise across the country revised them. Guidelines and recommendations for ICH management were described as simply as possible to allow more doctors to use them easily. We hope that our effort in developing the telemedicine protocols will ultimately improve the quality of ICH treatment in local emergency rooms in rural and underserved areas in Gangwon state.

An innovative method for detecting surgical errors using indocyanine green angiography during carotid endarterectomy: a preliminary investigation.

BACKGROUND: Carotid endarterectomy (CEA) is the most effective treatment method of carotid stenosis or occlusion. Surgeons typically check the blood flow in each vessel using Duplex Doppler ultrasonography or radiocontrast angiography in order to prevent postoperative complications. Embolic cerebral infarction on the ipsilateral side has been reported in 4-7% of patients undergoing CEA despite a tolerable blood flow reported by Duplex ultrasonography. This study was designed to evaluate a new intraoperative method for detecting technical errors during CEA using indocyanine green (ICG) angiography. METHODS: Six consecutive patients with severe carotid stenosis or occlusion underwent CEA. Both ICG angiography and Doppler ultrasonography were performed before the carotid arterial incision and after the carotid arterial suture. After injecting ICG dye via an intravenous route, the internal surface, atheroma, and flow defect were visualized with a microscope. RESULTS: In ICG angiography, stenotic lesions could be identified as regions of relatively dark signal intensity. Magnified real-time images could be created using a microscope with an infrared filter, including three-dimensional images and detailed images of the inner lumen. These images could then be compared with the results of Doppler ultrasonography. In the six cases assessed by both ICG angiography and Doppler ultrasonography, all Doppler results were acceptable. However, one patient underwent revision surgery because a fluttering atheroma was detected by ICG angiography. ICG angiography could assume the extent of severe stenotic area. ICG angiography could also detect mobile lesions such as a fluttering atheroma. CONCLUSIONS: Intraoperative ICG angiography before arteriotomy is useful to determine the precise stenotic area and the shape of the associated plaque. ICG angiography after an arteriotomy site is sutured is also useful for detecting residual stenosis or fluttering atheroma. ICG angiography could be an alternative method to Doppler ultrasonography for ensuring a complete and successful operation and preventing complications.

An Experimental Study on the Biomechanical Effectiveness of Bone Cement-Augmented Pedicle Screw Fixation with Various Types of Fenestrations.

OBJECTIVE: To analyze the effects of the number and shape of fenestrations on the mechanical strength of pedicle screws and the effects of bone cement augmentation (BCA) on the pull-out strength (POS) of screws used in conventional BCA. METHODS: For the control group, a conventional screw was defined as C1, a screw with cannulated end-holes was defined as C2, a C2 screw with six pinholes was defined as C3, and the control group type was set. Among the experimental screws, T1 was designed using symmetrically placed thru-hole type fenestrations with an elliptical shape, while T2 was designed with half-moon (HM)-shaped asymmetrical fenestrations. T3 and T4 were designed with single HM-shaped fenestrations covering three pitches and five pitches, respectively. T5 and T6 were designed with 0.6-mm and 1-mm wider fenestrations than T3. BCA was performed by injecting 3 mL of commercial bone cement in the screw, and mechanical strength and POS tests were performed according to ASTM F1717 and ASTM F543 standards. Synthetic bone (model #1522-505) made of polyurethane foam was used as a model of osteoporotic bone, and radiographic examinations were performed using computed tomography and fluoroscopy. RESULTS: In the fatigue test, at 75% ultimate load, fractures occurred 7781 and 9189 times; at 50%, they occurred 36122 and 82067 times; and at 25%, no fractures occurred. The mean ultimate load for each screw type was 219.1±52.39 N for T1, 234.74±15.9 N for T2, 220.70±59.23 N for T3, 216.45±32.4 N for T4, 181.55±54.78 N for T5, and 216.47±29.25 N for T6. In comparison with C1, T1, T2, T3, T4, and T6 showed significantly different ultimate load values (p<0.05). However, when the values for C2 and the fenestrated screws were evaluated with an unpaired t test, the ultimate load value of C2 significantly differed only from that of T2 (p=0.025). The ultimate load value of C3 differed significantly from those of T1 and T2 (C3 vs. T1 : p=0.048; C3 vs. T2 : p<0.001). Linear correlation analysis revealed a significant correlation between the fenestration area and the volume of bone cement (Pearson's correlation coefficient r=0.288, p=0.036). The bone cement volume and ultimate load significantly correlated with each other in linear correlation analysis (r=0.403, p=0.003). CONCLUSION: Fenestration yielded a superior ultimate load in comparison with standard BCA using a conventional screw. In T2 screws with asymmetrical two-way fenestrations showed the maximal increase in ultimate load. The fenestrated screws can be expected to show a stable position for the formation of the cement mass.