Long-term observation of antibody titers against SARS-CoV-2 following vaccination.

Objectives: We aimed to understand how SARS-CoV-2 antibody titer decrease following SARS-CoV-2 mRNA vaccination and to estimate the timing of booster vaccination. Study design: Six hundred sixty-two healthcare workers were administered with total of three doses of SARS-CoV-2 mRNA vaccine during the same short period. Of them, three volunteers were enrolled to measure anti-receptor binding domain (RBD) antibody titers (IgG) monthly following the second and the third doses. Methods: Serum anti-RBD antibody titers were measured monthly and the decay curve of the antibody was analyzed. We estimate the timing of the third and fourth vaccine based on the observed antibody titer decrease and the period of breakthrough infections in the vaccine recipients. Results: Anti-RBD antibody decreased exponentially following the 2nd dose. Between 108 and 117 days following the second dose, breakthrough infection of SARS-CoV-2 occurred in 11 out of the 662 vaccine recipients. Based on the decrease in anti-RBD antibody and the timing of the breakthrough infections, we estimate that the optimal timing of a third dose would be at earliest 108 days after the second dose, when anti-RBD antibody titers are less than 338 BAU/mL. The anti-RBD antibody titers were sustained relatively higher for 161 days following the third dose (416 days following the second dose). Conclusions: We estimate that the optimal timing of a third dose would be at earliest 108 days after the second dose, or anti-RBD antibody titers are less than 338 BAU/mL. We suggest that a fourth dose should be administered later than 161 days following the third dose.

Combination of Linagliptin and Empagliflozin Preserves Cardiac Systolic Function in an Ischemia-Reperfusion Injury Mice With Diabetes Mellitus.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitor (SGLT2i) and dipeptidyl peptidase 4 inhibitor (DPP4i) are oral hypoglycemic agents. Although SGLT2i has been shown having the beneficial effects on heart failure in basic and clinical studies, the combined effects of SGLT2i and DPP4i have not been established well. We investigated the effects of SGLT2i and DPP4i against diabetes mice model of myocardial ischemia-reperfusion injury. METHODS: Streptozotocin-induced diabetic C57BL/6J mice were divided into control (vehicle), empagliflozin (30 mg/kg/day), linagliptin (3 mg/kg/day) and combination (30 mg/kg/day and 3 mg/kg/day, respectively) groups. After 7 days of drug administration, 30 min of myocardial ischemia was performed. We investigated body weight, heart weight, blood glucose, and cardiac functions by pressure-volume Millar catheter followed by 28 days of additional drug administration. RESULTS: Blood glucose levels, body weight, and heart weight were not significantly different between the groups. In Millar catheter analysis, left ventricular volume at the peak left ventricular ejection rate which is one of the cardiac systolic parameters in combination group was significantly preserved than that in control (P = 0.036). The cardiac index in the combination group tended to be preserved compared to that in the control (P = 0.06). The pathological fibrotic area in the left ventricle in the combination group also tended to be smaller (P = 0.08). CONCLUSIONS: Combination therapy with linagliptin and empagliflozin preserved cardiac systolic function on the diabetes mice model of myocardial ischemia-reperfusion injury independent of blood glucose levels.

Fluorescence multispectral imaging-based diagnostic system for atherosclerosis.

BACKGROUND: Composition of atherosclerotic arterial walls is rich in lipids such as cholesterol, unlike normal arterial walls. In this study, we aimed to utilize this difference to diagnose atherosclerosis via multispectral fluorescence imaging, which allows for identification of fluorescence originating from the substance in the arterial wall. METHODS: The inner surface of extracted arteries (rabbit abdominal aorta, human coronary artery) was illuminated by 405 nm excitation light and multispectral fluorescence images were obtained. Pathological examination of human coronary artery samples were carried out and thickness of arteries were calculated by measuring combined media and intima thickness. RESULTS: The fluorescence spectra in atherosclerotic sites were different from those in normal sites. Multiple regions of interest (ROI) were selected within each sample and a ratio between two fluorescence intensity differences (where each intensity difference is calculated between an identifier wavelength and a base wavelength) from each ROI was determined, allowing for discrimination of atherosclerotic sites. Fluorescence intensity and thickness of artery were found to be significantly correlated. CONCLUSIONS: These results indicate that multispectral fluorescence imaging provides qualitative and quantitative evaluations of atherosclerosis and is therefore a viable method of diagnosing the disease.

A soluble form of human nectin-2 impairs exocrine secretion of pancreas and formation of zymogen granules in transgenic mice.

Transgenic mouse lines expressing a soluble form of human nectin-2 (hNectin-2Ig Tg) exhibited distinctive elevation of amylase and lipase levels in the sera. In this study, we aimed to clarify the histopathology and to propose the transgenic mouse lines as new animal model for characteristic pancreatic exocrine defects. The significant increase of amylase and lipase levels in sera of the transgenic lines approximately peaked at 8 weeks old and thereafter, plateaued or gradually decreased. The histopathology in transgenic acinar cells was characterized by intracytoplasmic accumulation of abnormal proteins with decrease of normal zymogen granules. The hNectin-2Ig expression was observed in the cytoplasm of pancreatic acinar cells, which was consistent with zymogen granules. However, signals of hNectin-2Ig were very weak in the transgenic acinar cells with the abnormal cytoplasmic accumulaion. The PCNA-positive cells increased in the transgenic pancreas, which suggested the affected acinar cells were regenerated. Acinar cells of hNectin-2Ig Tg had markedly small number of zymogen granules with remarkable dilation of the endoplasmic reticulum (ER) lumen containing abundant abnormal proteins. In conclusion, hNectin-2Ig Tg is proposed as a new animal model for characteristic pancreatic exocrine defects, which are due to the ER stress induced by expression of mutated cell adhesion molecule that is a soluble form of human nectin-2.

The Safety and Efficacy of Triple Antiplatelet Therapy after Intracranial Stent-Assisted Coil Embolization.

BACKGROUND: Stent-assisted coil embolization is effective for intracranial aneurysms, especially for wide-necked aneurysms; however, the optimal antiplatelet regimens for postoperative ischemic events have not yet been established. We aimed at determining the efficacy and safety of a triple antiplatelet therapy regimen after intracranial stent-assisted coil embolization. METHODS: We retrospectively evaluated patients who underwent stent-assisted coil embolization for unruptured intracranial aneurysms or during the chronic phase of a ruptured intracranial aneurysm (≥ 4 weeks after subarachnoid hemorrhage onset). We recorded the incidence of ischemic and bleeding events 140 days postoperatively. RESULTS: We assessed 79 cases in patients who received either dual (n = 51) or triple (n = 28) antiplatelet therapy. The duration of triple antiplatelet therapy was 49 ± 29 days. Seven patients in the dual group experienced postoperative ischemic events. Compared to the dual group, the triple group had a similar incidence of postoperative bleeding events but a significantly lower incidence of postoperative ischemic events (P < .05). CONCLUSIONS: Triple antiplatelet therapy had a significantly lower incidence of postoperative ischemic events and a similar incidence of postoperative bleeding events 140 days postoperatively.

[Unruptured cerebral aneurysm associated with fenestration of the anterior cerebral artery successfully treated with coil embolization using an intracranial stent: a case report].

Recent sporadic reports have described successful endovascular treatment of cerebral aneurysms associated with fenestration. We experienced an unruptured cerebral aneurysm case, with fenestration of the horizontal portion of the anterior cerebral artery that was successfully treated with coil embolization using an intracranial stent. An 80-year-old man presented with a chief complaint of gait disorder. Magnetic resonance imaging showed an incidental unruptured aneurysm. Three-dimensional digital subtraction angiography revealed a cerebral aneurysm associated with fenestration of the horizontal portion of the anterior cerebral artery. Endovascular surgery was performed at the patient's request. Conservation of the fenestrated vessels and perforators is important in the treatment of cerebral aneurysm associated with fenestration. Intracranial stents are reportedly useful for conserving not only parent vessels but also their perforators. In the present case, no postoperative perforator damage occurred. An endovascular approach is a potential treatment option with full evaluation of the relationship between the aneurysm and fenestrated vessels.

A manual carotid compression technique to overcome difficult filter protection device retrieval during carotid artery stenting.

BACKGROUND: We investigated the incidence of embolic protection device retrieval difficulties at carotid artery stenting (CAS) with a closed-cell stent and demonstrated the usefulness of a manual carotid compression assist technique. METHODS: Between July 2010 and October 2013, we performed 156 CAS procedures using self-expandable closed-cell stents. All procedures were performed with the aid of a filter design embolic protection device. We used FilterWire EZ in 118 procedures and SpiderFX in 38 procedures. The embolic protection device was usually retrieved by the accessory retrieval sheath after CAS. We applied a manual carotid compression technique when it was difficult to navigate the retrieval sheath through the deployed stent. We compared clinical outcomes in patients where simple retrieval was possible with patients where the manual carotid compression assisted technique was used for retrieval. RESULTS: Among the 156 CAS procedures, we encountered 12 (7.7%) where embolic protection device retrieval was hampered at the proximal stent terminus. Our manual carotid compression technique overcame this difficulty without eliciting neurologic events, artery dissection, or stent deformity. CONCLUSIONS: In patients undergoing closed-cell stent placement, embolic protection device retrieval difficulties may be encountered at the proximal stent terminus. Manual carotid compression assisted retrieval is an easy, readily available solution to overcome these difficulties.

Nε-(carboxymethyl)lysine in debris from carotid artery stenting: multiple versus nonmultiple postoperative lesions.

BACKGROUND: No predictor of postoperative ischemic events has been identified in patients undergoing carotid artery stenting (CAS). We aimed to determine whether N(ε)-(carboxymethyl)lysine (CML) in debris trapped by an embolic protection filter device is a predictor of postoperative ischemic events. METHODS: We enrolled 27 patients (73.4 ± 7.2 years; 22 male, 5 female) who underwent CAS for carotid artery stenosis. Diffusion-weighted magnetic resonance imaging was performed before and after the procedure. Protein samples were extracted from the debris. CML and myeloperoxidase were examined by solid phase enzyme-linked immunosorbent assay and Western blot analysis. RESULTS: Seventeen patients had 0 or 1 new lesion (nonmultiple lesions) postoperatively, whereas 10 patients had 2 or more new lesions postoperatively (multiple lesions). The CML concentration of the protein sample was significantly higher in patients with multiple lesions than in those with nonmultiple lesions (6.26 ± 2.77 ng/mg protein and 3.36 ± 1.57 ng/mg protein, respectively; P = .010). Statin therapy for dyslipidemia was associated with a lower incidence of multiple lesions and a lower concentration of CML in the protein sample (P = .004 and P = .02, respectively). Receiver operating characteristic analysis showed that the area under the curve for CML was significantly greater than .5 (.877; 95% confidence interval, .742-1.00). CONCLUSIONS: CML derived from debris may distinguish between patients with postoperative multiple ischemic lesions and those with postoperative nonmultiple lesions who undergo CAS.

Uncooled infrared camera for the noninvasive visualization of the vascular flow in an anastomotic vessel during neurological surgery: technical note.

We herein present our experience to assess intraoperative confirmation of vascular patency with an uncooled infrared camera in extracranial-intracranial (EC-IC) bypass surgery. This camera had distinguishing characteristics, including its small size, light weight, and adequate temperature resolution (< 0.022 degrees). We used a simplified zoom germanium lens as a preliminary study to verify the potential of using this camera to assess the vascular flow of the end-to-side anastomosis model in rats. In addition, we evaluated the vascular flow in continuous clinical series using this infrared camera during EC-IC bypass in 14 patients (17 sides). This infrared camera offers real-time information on the vascular patency of end-to-side anastomosis vessels of all relevant diameters. The spatial resolution and image quality are satisfactory, and the procedure can be safely repeatable. We have shown that the infrared camera could be a new and feasible technology for intraoperative imaging of the vascular flow and is considered to be clinically useful during cerebrovascular surgery.

Onset Time of Ischemic Events and Antiplatelet Therapy after Intracranial Stent-assisted Coil Embolization.

BACKGROUND: Stent-assisted coil embolization is effective for intracranial aneurysms, especially wide-necked aneurysms; however, the optimal antiplatelet regimens for ischemic events that develop after coil embolization have not yet been established. We aimed to determine the onset time of such postoperative ischemic events and the relationship between these events and antiplatelet therapy. METHODS: We performed coil embolization using a vascular reconstruction stent for 43 cases of intracranial aneurysms and evaluated the incidence of postoperative ischemic events in these cases. RESULTS: Nine patients showed postoperative ischemic events during the follow-up period (13 ± 7 months). Two patients developed cerebral infarction within 24 hours. Five patients developed transient ischemic attack within 40 days while they were receiving dual antiplatelet therapy. In addition, 1 patient showed cerebral infarction 143 days postoperatively during single antiplatelet therapy, and a case of transient visual disturbance was reported 191 days postoperatively (49 days after antiplatelet therapy had been discontinued). We increased the number of antiplatelet agents in 4 of these patients. The other 5 patients were under strict observation with dual antiplatelet therapy. All these patients were shifted to single antiplatelet therapy 3-13 months postoperatively. No recurrence of ischemic events was noted. CONCLUSIONS: Postoperative ischemic events are most likely to occur within 40 days postoperatively. For patients with postoperative ischemic events, additional ischemic events can be prevented by increasing the number of antiplatelet agents; subsequently, they can be shifted to single antiplatelet therapy after the risk of recurrence has decreased.

Treatment outcomes of carotid artery stenting with two types of distal protection filter device.

PURPOSE: Preventing cerebral embolism from debris produced during carotid artery stenting (CAS) is important. This study compared the treatment outcomes of CAS using two types of filter-based embolic protection devices currently in use in Japan. MATERIALS AND METHODS: We assessed 121 consecutive cases of CAS performed with FilterWire EZ™ between July 2010 and November 2012 and 37 consecutive cases of CAS performed with the Spider FX™ between November 2012 and June 2013. A Carotid Wallstent™ was used in all cases. The incidence of positive lesions on diffusion-weighted magnetic resonance imaging (DWI) and stroke were compared between the groups. RESULTS: Postoperative DWI-positive lesions were observed in 38 (31.4%) and 14 (37.8%) patients in the FilterWire and Spider groups, respectively. In the FilterWire group, complications were transient ischemic attacks in 3 (2.5%) patients, cerebral infarction in 2 (1.7%) patients (1 patient each with minor and major stroke), and cerebral hemorrhage due to hyperperfusion syndrome in 1 (0.8%) patient. In the Spider group, except for cerebral infarction (minor stroke) in 1 (2.7%) patient, no complications were observed. No significant differences were observed in the incidence of complications between the groups. CONCLUSION: FilterWire EZ and Spider FX are comparable in terms of treatment outcome.

An analysis of T2 mapping on brain tumors.

PURPOSE: Vasogenic edema on glioblastoma multiforme (GBM) or a metastatic brain tumor (METS) may have different T2 relaxation time values because it involves an increased water component. In this study, we assessed the diagnostic utility of T2 mapping techniques in distinguishing GBM from METS. MATERIALS AND METHODS: We studied a glioblastoma (GBM) patient and a metastatic brain tumor (METS) patient who had not undergone previous surgery or treatment. All MR imaging was carried out using a 3.0-T whole-body unit, and axial T2 maps were generated with five TEs (TE = 20, 40, 60, 80, and 100 ms). Data were analyzed by using image processing and analysis software. RESULTS: The T2 map of a GBM case showed that the -peritumoral area at a T2 relaxation time of 120-160 ms is prominent compared with the area at 210-240 ms. In contrast, the peritumoral area at 210-240 ms was prominent compared with the area at 120-160 ms in a METS case. CONCLUSION: The distribution of T2 relaxation time in the peritumoral area shows different patterns in glioblastomas and metastatic brain tumors.

Focal increase in cerebral blood flow after treatment with near-infrared light to the forehead in a patient in a persistent vegetative state.

OBJECTIVE: This study aimed to quantify the cerebral blood flow (CBF) after bilateral, transcranial near-infrared light-emitting diode (LED) irradiation to the forehead in a patient in a persistent vegetative state following severe head injury. BACKGROUND DATA: Positive behavioral improvement has been observed following transcranial near-infrared light therapy in humans with chronic traumatic brain injury and acute stroke. METHODS: Single-photon emission computed tomography with N-isopropyl-[123I]p-iodoamphetamine (IMP-SPECT) was performed following a series of LED treatments. RESULTS: IMP-SPECT showed unilateral, left anterior frontal lobe focal increase of 20%, compared to the pre-treatment value for regional CBF (rCBF) for this area, following 146 LED treatments over 73 days from an array of 23×850 nm LEDs, 13 mW each, held 5 mm from the skin, 30 min per session, the power density 11.4 mW/cm(2); the energy density 20.5 J/cm(2) at the skin. The patient showed some improvement in his neurological condition by moving his left arm/hand to reach the tracheostomy tube, post-LED therapy. CONCLUSIONS: Transcranial LED might increase rCBF with some improvement of neurological condition in severely head-injured patients. Further study is warranted.

A ruptured internal carotid artery aneurysm located at the origin of the duplicated middle cerebral artery associated with accessory middle cerebral artery and middle cerebral artery aplasia.

BACKGROUND: Intracranial vascular anomalies involving the middle cerebral artery (MCA) are relatively rare, as such knowledge will be helpful for planning the optimal surgical procedures. CASE DESCRIPTION: We herein present the first case of a ruptured internal carotid artery aneurysm arising at the origin of the hypoplastic duplicated MCA associated with accessory MCA and main MCA aplasia, which was revealed by angiograms and intraoperative findings. CONCLUSION: In practice, this case highlights the urgent need to preoperatively recognize such vascular anomalies as well as understand the collateral blood supply in cerebral ischemia associated with these MCA anomalies.

Simple rabbit model of vulnerable atherosclerotic plaque.

The present study investigated the appropriate conditions for induction of lesions in the rabbit atherosclerosis model. Four-week-old male Japanese white rabbits (n = 19) were fed the high cholesterol diet (HCD). This group was classified as the early start (ES) group. The animals were divided into three groups: (i) 1% HCD group (n = 8), (ii) 2% HCD group (n = 8), and (iii) normal diet group (control, n = 3). The HCD groups were divided into two subgroups: (a) balloon injury (BI) group (1% HCD, n = 5; 2% HCD, n = 4), and (b) non-BI group (1% HCD, n = 3; 2% HCD, n = 4). Survival period, histological characteristics, area of plaque, and effects of BI and diet cholesterol content were analyzed. Twelve-week-old male Japanese white rabbits (n = 8) were fed the 1% HCD. This group was classified as the late start (LS) group, and underwent BI in the aorta. The histological characteristics and area of plaque were investigated. The plaque satisfied the three requirements of vulnerable plaque: Lipid rich core, accumulation of macrophages, and thin fibrous cap. The plaque area was significantly greater in the ES group compared to the LS group (p = 0.0037). Survival analysis found no statistical correlation with BI or diet cholesterol content. This study indicates that the simplest conditions for inducing the rabbit atherosclerosis model are 1% HCD, non-BI, and early start of HCD. This model is suitable for experiments with new therapeutic devices.

Successful treatment of a thrombosed posterior cerebral artery aneurysm causing obstructive hydrocephalus.

The authors report a 49-year-old man who presented with obstructive hydrocephalus caused by a thrombosed posterior cerebral artery aneurysm. He underwent an endoscopic third ventriculostomy for the obstructive hydrocephalus followed by endovascular occlusion for the aneurysm. To our knowledge, this is the first report of a thrombosed posterior cerebral artery aneurysm presenting with obstructive hydrocephalus treated by the combination of endoscopic and endovascular techniques.

Effectiveness of narrow-band ultraviolet-B phototherapy for prevention of intimal hyperplasia in a rat carotid balloon injury model.

BACKGROUND AND OBJECTIVE: Narrow-band ultraviolet-B light (NBUVB) (313 nm) is known to have anti-proliferative effects, implying a potential treatment for intimal hyperplasia, but it remains to be ascertained. We assessed the effects of NBUVB irradiation for prevention of intimal hyperplasia. STUDY DESIGN/MATERIALS AND METHODS: The rat carotid arteries were irradiated with NBUVB after balloon injury (BI), and the degree of intimal hyperplasia was histopathologically assessed. The anti-proliferative effects using cultured human smooth muscle cells were evaluated by flow cytometry and immunoblot analysis. RESULTS: NBUVB (0.3-4.5 J/cm(2)) irradiation immediately after BI reduced the degree of intimal hyperplasia at 14 and 28 days after BI (P<0.001) without any obvious complications. Neither an increase in the number of medial cells nor upregulation of proliferating cell nuclear antigen was observed in the irradiated arteries. NBUVB irradiation at 2 or 14 days after BI significantly suppressed further intimal hyperplasia (P<0.01). NBUVB-irradiated cultured cells showed inhibited proliferation involved with G(1) and G(2)/M arrests. Increased expression of p53 and inhibition of retinoblastoma protein (pRB) phosphorylation were also seen in the NBUVB-irradiated cells. CONCLUSIONS: These data suggest that NBUVB irradiation is an effective method for preventing intimal hyperplasia. The anti-proliferative effect is partly due to the cell cycle arrest caused by p53 expression and inhibited pRB phosphorylation.

The relationship between venous hypertension and expression of vascular endothelial growth factor: hemodynamic and immunohistochemical examinations in a rat venous hypertension model.

BACKGROUND: Venous hypertension is regarded as an important factor in the pathogenesis of dural arteriovenous fistula (DAVF). We investigate histologic reaction of dural sinus under the condition of venous hypertension using a rat venous hypertension model to present hemodynamic and immunohistochemical effect in the development of DAVF. METHODS: Twenty-four Sprague-Dawley male rats were divided into venous hypertension and control groups. Venous hypertension was induced with a left common carotid artery-external jugular vein anastomosis and an occlusion of a right posterior facial vein. Measurements of systemic mean arterial pressure, draining vein pressure (DVP), and cerebral perfusion pressure (CPP) were conducted on the next day, at 7 days, and at 28 days after surgery, and the rats were killed for histologic examinations. RESULTS: Postoperative DVP increased significantly in venous hypertension group compared to control group (35 +/- 5 vs 13 +/- 2 mm Hg, P < .05). Increased DVP remained above 30 mm Hg throughout the observation period. Postoperative CPP decreased significantly in venous hypertension group compared to control group (49 +/- 8 vs 86 +/- 9 mm Hg, P < .05). In venous hypertension group, there was a significant difference between days 1 and 28 (49 +/- 8 vs 64 +/- 8 mm Hg, P < .05). Histologic examination revealed thickening of connective tissues, proliferation of fibroblasts, and strong expression of vascular endothelial growth factor (VEGF) in endothelium under venous hypertension condition. Immunostained VEGF cells decreased significantly from day 7 to day 28 (100 +/- 16 vs 72 +/- 19 cells, P < .05). A positive correlation was observed between DVP and VEGF expression (Pearson correlation coefficient; r = 0.671, P = .0017). There was a negative correlation between CPP and immunostained VEGF cells (r = -0.702, P = .0089). CONCLUSIONS: These results suggest that venous hypertension is associated with increased expression of VEGF, and a decreased CPP may have a potential effect in VEGF expression under venous hypertension condition. These factors are speculated to play an important role in progression of DAVF.

[An animal model of posttraumatic stress disorder and its validity: effect of paroxetine on a PTSD model in rats].

To better understand neuroscientific aspects of posttraumatic stress disorder (PTSD), it is necessary to establish an animal model of PTSD in which behavioral changes persist after initial traumatization. We administered inescapable footshock (IS) to male Wistar rats in a shuttle-box (inescapable stress session), and after 2 weeks we performed an avoidance/escape task session in the shuttle-box using signal lights as anxiogenic external stimuli. Rats exposed to IS beforehand exhibited PTSD-like bi-directional behavioral changes, that is, "avoidance/numbing" (e.g. decreased activity, reactivity, and interest in surroundings) and "hyperarousal" (e.g. irritability and exaggerated responsiveness to external stimuli). Concretely speaking, in a relatively calm situation, spontaneous locomotion decreased during a 5-min adaptation period just before the avoidance/escape task session. On the other hand, in a stressful situation after starting the task session, not only avoidance responses to external stimuli (signal lights) but also gate-crossings during inter-trial interval increased. Accordingly, the paradigm used here could serve as a useful model of PTSD. We administered paroxetine (PRX) to rats just after IS for 2 weeks to examine its chronic effect on our animal model. Two weeks of PRX treatment significantly reduced hyperarousal-like behaviors, but no effect on avoidance/numbing-like ones was manifested.