Risk factors for CAR-T cell manufacturing failure among DLBCL patients: A nationwide survey in Japan.

For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 104 /µL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3-24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105 /µL; p = 0.022) or low CD4/CD8 ratios (

Efficacy and Safety of Gastrointestinal Tumour Site Marking with da Vinci-Compatible Near-Infrared Fluorescent Clips: A Case Series.

BACKGROUND: The conventional near-infrared fluorescent clip (NIRFC) ZEOCLIP FS® has been used successfully in marking tumour sites during laparoscopic surgeries. However, this clip is difficult to observe with the Firefly imaging system equipped with the da Vinci® surgical system. We have been involved in the modification of ZEOCLIP FS® and development of da Vinci-compatible NIRFC. This is the first prospective single-centre case series study verifying the usefulness and safety of the da Vinci-compatible NIRFC. METHODS: Twenty-eight consecutive patients undergoing da Vinci®-assisted surgery for gastrointestinal cancer (16 gastric, 4 oesophageal, and 8 rectal cases) between May 2021 and May 2022 were enrolled. RESULTS: Tumour location was identified by the da Vinci-compatible NIRFCs in 21 of 28 (75%) patients, which involved 12 gastric (75%), 4 oesophageal (100%), and 5 rectal (62%) cancer cases. No adverse events were observed. CONCLUSION: Tumour site marking with da Vinci-compatible NIRFC was feasible in 28 patients enrolled in this study. Further studies are warranted to substantiate the safety and improve the recognition rate.

The impact of the quantitative assessment procedure for coronary artery bypass graft evaluations using high-resolution near-infrared fluorescence angiography.

PURPOSE: Near-infrared angiography (NIR) is used for on-site graft assessment during coronary artery bypass grafting. This study evaluated the results of a quantitative NIR assessment using a new high-resolution NIR device (h-NIR) for graft assessment. METHODS: Forty-three patients were enrolled in our study. Internal thoracic artery (ITA) grafts anastomosed to the left anterior descending artery and examined intraoperatively using h-NIR were included. The ITA grafts were divided into 2 groups for a comparative analysis: patent grafts (P group; n = 37) and failed grafts (F group; n = 6). The graft flow was evaluated by a "quantitative NIR assessment", and the fluorescence luminance intensity (FLI) was measured. Direct observation of the graft and anastomosis with h-NIR was also performed. RESULTS: The FLI was higher in the P group than in the F group. The receiver operating characteristic analysis revealed the following cut-off values for FLIs depending on imaging duration: 21.1% at 1 s, 35.5% at 2 s, 58.4% at 3 s, and 83.3% at 4 s. The sensitivity and specificity for detecting graft failure were 83.3% and 69.8-80.6%, respectively. Furthermore, h-NIR was also able to visualize arterial dissection in ITA grafts. CONCLUSIONS: A quantitative NIR assessment with an h-NIR device can improve the detectability of anastomotic stenosis, and h-NIR successfully detected arterial dissection of grafts.

Near-infrared fluorescent solid material for visualizing indwelling devices implanted for medical use.

BACKGROUND: In clinical practice, various devices are implanted into the body for medical reasons. As X-ray fluoroscopy is necessary to visualize medical devices implanted into the body, the development of a less-invasive visualization method is highly desired. This study aimed to investigate the clinical applicability of our novel solid material that emits near-infrared fluorescence. METHODS: We developed a solid resin material that emits near-infrared fluorescence. This material incorporates a near-infrared fluorescent pigment, with quantum yield ≥ 20 times than that of indocyanine green. It can be sterilized for medical treatment. This resin material is designed to be molded into a catheter and inserted into the body with an endoscope clip. In this preclinical experiment using a swine model, the resin material was embedded into the body of the swine and visualized with a near-infrared fluorescence camera system. RESULTS: Endoscopic clips were placed in the mucosa of the stomach, esophagus, and large intestine, and the indwelling ureteral catheters were successfully visualized by near-infrared fluorescence laparoscopy. CONCLUSIONS: We confirmed the tissue permeability of the fluorescence emitted by our novel near-infrared fluorescent material and the possibility of its clinical application. This material may allow visualization of devices embedded in the body.

Novel endoscopic marking clip equipped with resin-conjugated fluorescent indocyanine green during laparoscopic surgery for gastrointestinal cancer.

PURPOSE: Intraoperative identification of the cancer location is often difficult to conduct during laparoscopic surgery, especially in early-stage cancers. This study aimed to investigate the feasibility and accuracy of a novel endoscopic clip resin-conjugated fluorescent indocyanine green during laparoscopic surgery for gastrointestinal cancer. METHODS: Preoperative placement of endoscopic marking clips equipped with resin-conjugated fluorescent indocyanine green was performed to determine the resection margin in eight patients with gastrointestinal cancer. During laparoscopic surgery, a dedicated laparoscopic system with a xenon light source was used to detect fluorescence. The evaluation determined whether the fluorescent from the clips was visualized during laparoscopic surgery. RESULTS: Fluorescent signal emitted from ICG in the resin of the clips was detected in six patients from the outer layer of the serosal surfaces of the gastrointestinal tract, and the clips aided in accurate resection line of the organ. There were no significant differences of age, gender, and BMI between the patients in whom we could and could not detect ICG fluorescence. CONCLUSIONS: The results demonstrated the usefulness of a novel clip-equipped fluorescent resin, which is a promising diagnostic tool to detect accurate tumor location during laparoscopic surgery.

Influence of residual coronary flow on bypass graft flow for graft assessment using near-infrared fluorescence angiography.

PURPOSE: Near-infrared fluorescence angiography (NIR) detects the attenuation of fluorescence luminance intensity (FLI) through coronary artery bypass grafts affected by anastomotic stenosis. This study investigates the influence of residual blood flow of the host coronary artery (Ho) on bypass graft (Gr) FLI using a coronary artery bypass (CABG) model. METHODS: A mock circuit system was created using artificial vessels and artificial blood was supplied to the Gr and the Ho. We used NIR to examine the changes in FLI through the Gr. RESULTS: The Gr FLI was significantly attenuated according to the degree of Gr stenosis. The Gr FLI did not differ significantly among all degrees of Ho stenosis. High FLI grafts included grafts with degrees of Gr stenosis ≤ 75%, regardless of the severity of Ho stenosis. Moderate and low FLI grafts had 90 or 99% Gr stenosis, regardless of the severity of Ho stenosis. Gr FLI with 99% Gr stenosis was higher in 99% Ho stenosis than in ≤ 90% Ho stenosis. CONCLUSIONS: A high Gr FLI indicated the absence of ≥ 90% stenosis in the anastomosis and a low Gr FLI indicated severe stenosis in the anastomosis despite Ho stenosis. High Ho stenosis may prevent the attenuation of Gr FLI in severely stenosed grafts.

Evolution of photodynamic medicine based on fluorescence image-guided diagnosis using indocyanine green and 5-aminolevulinic acid.

New diagnostic techniques based on photodynamic medicine, such as near-infrared fluorescence using indocyanine green (NIR-ICG) and 5-aminolevulinic acid-mediated photodynamic diagnosis (ALA-PDD), are aiding navigation tasks across various fields of surgery. Specifically, NIR-ICG is being used for the intraoperative identification of sentinel lymph nodes or blood vessels in organ resection and for blood flow evaluation in surgery. These ICG-fluorescent imaging techniques could provide an additional and potentially valuable way to identify vascular and lymphatic structures in surrounding tissue. 5-Aminolevulinic acid is a precursor of a photosensitizing substance with affinity for tumors; thus, diagnostic laparoscopy using ALA-PDD in combination should improve the accuracy of detecting peritoneal dissemination in patients with advanced gastric cancer. The ability to overlay fluorescent imaging with conventional color images in real time using ALA-PDD and NIR with ICG would be of immense benefit to surgeons, providing good visualization and detection of target lesions not seen with the naked eye. A multi-center clinical study examining the safety and efficacy of ALA-PDD during laparoscopic examination for patients with advanced gastric cancer is currently underway in the form of doctor-initiated trials, and further verification studies will be conducted. Such imaging capability could have broad potential across cancer and vascular surgery.

Nasal Cavity of Green Sea Turtles Contains 3 Independent Sensory Epithelia.

The morphological and histological features of the nasal cavity are diverse among animal species, and the nasal cavities of terrestrial and semiaquatic turtles possess 2 regions lined with each different type of sensory epithelium. Sea turtles can inhale both of volatile and water-soluble odorants with high sensitivity, but details of the architectural features and the distribution of the sensory epithelia within the sea turtle nasal cavity remain uncertain. The present study analyzed the nasal cavity of green sea turtles using morphological, computed tomographic, and histological methods. We found that the middle region of the sea turtle nasal cavity is divided into anterodorsal, anteroventral, and posterodorsal diverticula and a posteroventral excavation by connective tissue containing cartilages. The posterodorsal diverticulum was lined with a thin sensory epithelium, and the anterodorsal and anteroventral diverticula were occupied by a single thick sensory epithelium. In addition, a relatively small area on the posteroventral excavation was covered by independent sensory epithelium that differed from other 2 types of epithelia, and a single thin bundle derived from the posteroventral excavation comprised the most medial nerve that joins the anterior end of the olfactory nerve tract. These findings suggested that the posteroventral excavation identified herein transfers stimuli through an independent circuit and plays different roles when odorants arise from other nasal regions.

Evaluation of graft anastomosis using time-intensity curves and quantitative near-infrared fluorescence angiography during peripheral arterial bypass grafting.

Near-infrared fluorescence angiography (NIR) visualizes blood perfusion using the fluorescence property of indocyanine green (ICG). This study aimed to retrospectively determine the usefulness of a quantitative analysis using NIR to predict the patency of peripheral arterial bypass grafts by measuring their fluorescence luminance intensities (FLIs).Thirteen grafts in 11 patients who underwent peripheral arterial bypass grafting were divided into a patent graft group (n = 7) and a failed graft group (n = 6). The changes in the FLIs of ICG opacification through the graft and distal host artery were retrospectively analyzed using stored NIR data. The time-intensity curves (TICs) of ICG opacification through the graft (Qgraft) and distal host artery (Qdistal) were measured. Two parameters, Δ(Qgraft - Qdistal) and integral(Qgraft - Qdistal), were also analyzed.Although not significant, decreases in Qgraft were observed in the failed graft groups. The Qdistal of the failed graft group was significantly attenuated as compared with that of the patent graft group. Δ(Qgraft - Qdistal) increased only in the failed graft group, which indicates widening of the gap in FLI. Integral(Qgraft - Qdistal) was higher in the failed graft group, as it reflects the accumulation of ICG opacification.The TICs were influenced by anastomotic stenosis in the distal site of the host arteries. Our results indicate that the comparison of Δ(Qgraft - Qdistal) and integral (Qgraft - Qdistal) quantitatively analyzed using NIR can potentially predict anastomotic stenosis.

3D topology of orientation columns in visual cortex revealed by functional optical coherence tomography.

Orientation tuning is a canonical neuronal response property of six-layer visual cortex that is encoded in pinwheel structures with center orientation singularities. Optical imaging of intrinsic signals enables us to map these surface two-dimensional (2D) structures, whereas lack of appropriate techniques has not allowed us to visualize depth structures of orientation coding. In the present study, we performed functional optical coherence tomography (fOCT), a technique capable of acquiring a 3D map of the intrinsic signals, to study the topology of orientation coding inside the cat visual cortex. With this technique, for the first time, we visualized columnar assemblies in orientation coding that had been predicted from electrophysiological recordings. In addition, we found that the columnar structures were largely distorted around pinwheel centers: center singularities were not rigid straight lines running perpendicularly to the cortical surface but formed twisted string-like structures inside the cortex that turned and extended horizontally through the cortex. Looping singularities were observed with their respective termini accessing the same cortical surface via clockwise and counterclockwise orientation pinwheels. These results suggest that a 3D topology of orientation coding cannot be fully anticipated from 2D surface measurements. Moreover, the findings demonstrate the utility of fOCT as an in vivo mesoscale imaging method for mapping functional response properties of cortex in the depth axis. NEW & NOTEWORTHY We used functional optical coherence tomography (fOCT) to visualize three-dimensional structure of the orientation columns with millimeter range and micrometer spatial resolution. We validated vertically elongated columnar structure in iso-orientation domains. The columnar structure was distorted around pinwheel centers. An orientation singularity formed a string with tortuous trajectories inside the cortex and connected clockwise and counterclockwise pinwheel centers in the surface orientation map. The results were confirmed by comparisons with conventional optical imaging and electrophysiological recordings.

A Novel Color Fluorescence Navigation System for Intraoperative Transcutaneous Lymphatic Mapping and Resection of Sentinel Lymph Nodes in Breast Cancer: Comparison with the Combination of Gamma Probe Scanning and Visible Dye Methods.

BACKGROUND: This study evaluated the clinical efficacy of a novel imaging system (HyperEye Medical System [HEMS]; Mizuho Corp., Tokyo, Japan) that uses the near-infrared (NIR) fluorescence of indocyanine green to analyze sentinel lymph node (SLN) biopsies for the staging of breast cancer. METHODS: This study enrolled 91 patients with histologically confirmed breast cancer that was clinically node negative with a tumor size <3 cm. We compared SLN identification rates between HEMS and conventional methods (gamma probe scanning using a colloidal radioisotope [RI] and a blue dye method) by analyzing the relationships of lymphatic to axillary lesions and SLNs. RESULTS: The identification rate of SLNs was 100% using HEMS, 97.8% using the RI method, and 95.6% using the blue dye method. Two types of lymphatic pathway (LP) were detected in 39 patients (42.9%) and also clearly identified using HEMS-captured color and NIR fluorescence. The incidence of two or more SLNs was significantly higher in patients with a two-route LP to the axilla group than in those with only one route (p < 0.001; 43.6 vs. 9.6%). CONCLUSIONS: The HEMS NIR fluorescence color imaging method is a promising potential modality for higher-level identification of SLNs than a standard combination of the RI and blue dye methods.

Clinical application of photodynamic medicine technology using light-emitting fluorescence imaging based on a specialized luminous source.

The natural amino acid 5-aminolevulinic acid (ALA) is a protoporphyrin IX (PpIX) precursor and a new-generation photosensitive substance that accumulates specifically in cancer cells. When indocyanine green (ICG) is irradiated with near-infrared (NIR) light, it shifts to a higher energy state and emits infrared light with a longer wavelength than the irradiated NIR light. Photodynamic diagnosis (PDD) using ALA and ICG-based NIR fluorescence imaging has emerged as a new diagnostic technique. Specifically, in laparoscopic examinations for serosa-invading advanced gastric cancer, peritoneal metastases could be detected by ALA-PDD, but not by conventional visible-light imaging. The HyperEye Medical System (HEMS) can visualize ICG fluorescence as color images simultaneously projected with visible light in real time. This ICG fluorescence method is widely applicable, including for intraoperative identification of sentinel lymph nodes, visualization of blood vessels in organ resection, and blood flow evaluation during surgery. Fluorescence navigation by ALA-PDD and NIR using ICG imaging provides good visualization and detection of the target lesions that is not possible with the naked eye. We propose that this technique should be used in fundamental research on the relationship among cellular dynamics, metabolic enzymes, and tumor tissues, and to evaluate clinical efficacy and safety in multicenter cooperative clinical trials.

Sex Differences and the Heritability of Scute Pattern Abnormalities in the Green Sea Turtle from the Ogasawara Archipelago, Japan.

Although scute pattern abnormalities in sea turtle species are considered to be strongly correlated with survival rate, there is little information available regarding these abnormalities and the primary cause for their development is unclear. For the conservation of sea turtle species, accumulating basic knowledge of scute pattern abnormalities is a fundamental step towards a better understanding of the causes of these abnormalities. In the present study, we counted vertebral and costal scutes from adults hunted for food (male and female) (n = 899), nesting females (n = 155), and hatchlings (n = 44,537) of the green sea turtle (Chelonia mydas) from the Ogasawara Archipelago, Japan. We found that the frequency of turtles with non-modal scute patterns was significantly greater in adult females than that in adult males (P = 0.02). Since females are produced by warmer incubation temperatures, and the period of sex determination coincides with the period of scute pattern determination, high incubation temperatures may be responsible for the induction of scute pattern abnormalities. Moreover, females with non-modal scute patterns produced a higher frequency of hatchlings with non-modal scute patterns than females with modal scute patterns (P < 0.01), indicating that scute abnormality may be heritable. For conservation of this species, our results suggest that decrease of the incubation temperature by cooling methods, such as provision of shade, may minimize the frequency of non-modal scute patterns, with consideration for the natural sex ratio.

Quantitative assessment technique of HyperEye medical system angiography for coronary artery bypass grafting.

PURPOSE: The HyperEye Medical System (HEMS) uses indocyanine green (ICG) to visualize blood vessels in coronary artery bypass grafting (CABG). We performed quantitative HEMS assessment to detect grafts at risk of occlusion. METHODS: We assessed the HEMS angiograms of 177 grafts from 69 patients who underwent CABG and compared the results with those of fluoroscopic coronary angiography, by measuring the increasing rate of ICG intensity, average acceleration value, and time to peak luminance intensity. RESULTS: Grafts in the patent and failed groups showed significant differences in their increasing rate of intensity and average acceleration value. The average accelerations value of ICG intensity of internal thoracic artery (ITA) and saphenous vein (SV) grafts were 112.3 and 144.9 intensity/s2 in the patent group, and 71.0 and 91.8 intensity/s2 in the failed group. The time to peak luminance intensity was 1.7 and 1.4 s in the patent group and 2.3 and 1.9 s in the failed group; these values were not significantly different. CONCLUSION: Significant reductions in the ICG intensity rate and average acceleration value can occur in failed grafts. Therefore, quantifiable changes in ICG intensity may help detect minute changes in blood flow.

Influence of vessel stenosis on indocyanine green fluorescence intensity assessed by near-infrared fluorescence angiography.

PURPOSE: Although useful for visualizing blood flow during revascularization surgery, the permeability of near-infrared fluorescence (NIR) angiography using indocyanine green (ICG) does not allow for vessel stenosis visualization. We hypothesized that changes in ICG fluorescence intensity reflect vessel stenosis, and evaluated the influence of stenosis on blood flow by ex vivo experimentation. METHODS: The vessel stenosis model comprised a silicon tube, a graft occluder, and artificial blood. During near-infrared angiography, the fluorescense intensity was calculated during pre- and post-stenosis of an artificial circuit, using a NIR angiography. We measured the maximum fluorescence intensity and the time to maximum fluorescence intensity. RESULTS: Severe stenosis (≥75%) attenuated the increase in ICG fluorescence intensity in the tube significantly, pre- and post-stenosis. The time to maximum fluorescence intensity did not differ between sites pre- and post-stenosis, irrespective of stenosis severity. CONCLUSION: Stenosis affected the ICG fluorescence intensity through the vessel. Thus, quantitative analysis using NIR angiography may detect severe vessel stenosis (≥75%), and the extinction curve of indocyanine fluorescence intensity may support the evaluation of blood flow. The absence of differences in the time to maximum fluorescence intensity for degrees of stenosis might suggest a limitation of previous conventional qualitative assessments.

(Near-Infrared) Fluorescence-Guided Surgery Under Ambient Light Conditions: A Next Step to Embedment of the Technology in Clinical Routine.

BACKGROUND AND PURPOSE: In open surgery procedures, after temporarily dimming the lights in the operation theatre, the Photo Dynamic Eye (PDE) fluorescence camera has, amongst others, been used for fluorescence-guided sentinel node (SN) biopsy procedures. To improve the clinical utility and logistics of fluorescence-guided surgery, we developed and evaluated a prototype modified PDE (m-PDE) fluorescence camera system. METHODS: The m-PDE works under ambient light conditions and includes a white light mode and a pseudo-green-colored fluorescence mode (including a gray-scaled anatomical background). Twenty-seven patients scheduled for SN biopsy for (head and neck) melanoma (n = 16), oral cavity (n = 6), or penile (n = 5) cancer were included. The number and location of SNs were determined following an indocyanine green-(99m)Tc-nanocolloid injection and preoperative imaging. Intraoperatively, fluorescence guidance was used to visualize the SNs. The m-PDE and conventional PDE were compared head-to-head in a phantom study, and in seven patients. In the remaining 20 patients, only the m-PDE was evaluated. RESULTS: Phantom study: The m-PDE was superior over the conventional PDE, with a detection sensitivity of 1.20 × 10(-11) M (vs. 3.08 × 10(-9) M) ICG in human serum albumin. In the head-to-head clinical comparison (n = 7), the m-PDE was also superior: (i) SN visualization: 100 versus 81.4 %; (ii) transcutaneous SN visualization: 40.7 versus 22.2 %; and (iii) lymphatic duct visualization: 7.4 versus 0 %. Findings were further underlined in the 20 additionally included patients. CONCLUSION: The m-PDE enhanced fluorescence imaging properties compared with its predecessor, and provides a next step towards routine integration of real-time fluorescence guidance in open surgery.

Electromyographic analysis of thigh muscles during track cycling on a velodrome.

We aimed to investigate neuromuscular activation of thigh muscles during track cycling at various speeds. Eight male competitive cyclists volunteered to participate in this study. Surface electromyography of the vastus lateralis, biceps femoris and adductor magnus muscles of the bilateral legs was recorded during track cycling on velodromes with a 250-m track. The participants were instructed to maintain three different lap times: 20, 18 and 16 s. The average rectified value (ARV) was calculated from the sampled surface electromyography. Significantly higher ARVs were observed in the right compared to left leg for the biceps femoris muscle during both straight and curved sections at 18- and 16-s lap times (P < 0.05). In the biceps femoris muscle, significant changes in ARVs during the recovery phase with an increase in speed were seen in the right leg only (P < 0.05). There were no significant differences in ARVs between the straight and curved sections for all three muscles (P > 0.05). From our findings, it was suggested that during track cycling on a velodrome the laterality of the biceps femoris muscle activity is a key strategy to regulate the speed, and fixed neuromuscular strategies are adopted between straight and curved sections for thigh muscles.

Acetylcholine Suppresses Ventricular Arrhythmias and Improves Conduction and Connexin-43 Properties During Myocardial Ischemia in Isolated Rabbit Hearts.

INTRODUCTION: Acetylcholine (ACh), a vagal efferent neurotransmitter, markedly improves survival in rats with myocardial ischemia (MI) by preventing ischemic loss of gap junction (Gj) and by inducing anti-apoptotic cascades. However, electrophysiological mechanisms of the antiarrhythmic effect of ACh after acute MI are still unclear. METHODS: Acute MI was induced by ligation of the left anterior descending (LAD) coronary artery in Langendorff-perfused rabbit hearts with (ACh(+):n = 11) or without (ACh(-):n = 12) 10 µmol/L ACh delivered continuously starting at 5 minutes before LAD ligation. Action potentials on the left ventricular (LV) anterior surface (≈2×2 cm) were recorded by optical mapping during pacing from the LV epicardium (BCL = 500 milliseconds). Conduction velocities (CVs) at 256 sites were calculated and the ventricular tachycardia/ventricular fibrillation (VT/VF) susceptibility was also assessed by programmed electrical stimulation before and 30 minutes after MI. The amount and distribution of Gj protein connexin-43 was analyzed by immunoblotting and immunohistochemistry. RESULTS: Averaged CV in the ischemic border zone (IBZ) was significantly slower in ACh(-) than in ACh(+) (21 ± 7 vs. 34 ± 6 cm/s; P < 0.01). Short-coupled extra stimulus further decreased CV of IBZ in ACh(-) (13 ± 4 cm/s) but did not change that in ACh(+) (34 ± 5 cm/s), leading to a high incidence of conduction block in IBZ in ACh(-) but not in ACh(+) (83% vs. 0%). VT/VF after MI were induced in ACh(-) but suppressed in ACh(+) (10/12 vs. 3/11; P < 0.01). Connexin-43 in the LV anterior wall was significantly reduced after MI in ACh(-) but not in ACh(+). CONCLUSION: ACh may suppress VT/VF by preventing loss of Gj and improving CV in IBZ during acute MI.

Human CD1c⁺ myeloid dendritic cells acquire a high level of retinoic acid-producing capacity in response to vitamin D3.

All-trans-retinoic acid (RA) plays a critical role in maintaining immune homeostasis. Mouse intestinal CD103⁺ dendritic cells (DCs) produce a high level of RA by highly expressing retinal dehydrogenase (RALDH)2, an enzyme that converts retinal to RA, and induce gut-homing T cells. However, it has not been identified which subset of human DCs produce a high level of RA. In this study, we show that CD1c⁺ blood myeloid DCs (mDCs) but not CD141(high) mDCs or plasmacytoid DCs exhibited a high level of RALDH2 mRNA and aldehyde dehydrogenase (ALDH) activity in an RA- and p38-dependent manner when stimulated with 1α,25-dihydroxyvitamin D3 (VD3) in the presence of GM-CSF. The ALDH activity was abrogated by TLR ligands or TNF. CD103⁻ rather than CD103⁺ human mesenteric lymph node mDCs gained ALDH activity in response to VD3. Furthermore, unlike in humans, mouse conventional DCs in the spleen and mesenteric lymph nodes gained ALDH activity in response to GM-CSF alone. RALDH2(high) CD1c⁺ mDCs stimulated naive CD4⁺ T cells to express gut-homing molecules and to produce Th2 cytokines in an RA-dependent manner. This study suggests that CD1c⁺ mDCs are a major human DC subset that produces RA in response to VD3 in the steady state. The "vitamin D-CD1c⁺mDC-RA" axis may constitute an important immune component for maintaining tissue homeostasis in humans.