Non-Pure Intestinal Phenotype as an Indicator of Progression in Sporadic Nonampullary Duodenal Adenomas: A Multicenter Retrospective Cohort Study.

INTRODUCTION: We aimed to evaluate the natural course of sporadic nonampullary duodenal adenomas (SNDAs) and determine the risk factors of progression. METHODS: We retrospectively analyzed the follow-up outcomes of patients with biopsy-diagnosed SNDA between April 2010 and March 2016 at 13 institutions. All initial biopsy specimens were centrally evaluated. Only those diagnosed with adenomas were included. Mucinous phenotypes were classified into pure intestinal and non-pure intestinal phenotypes. Cumulative incidence rates of carcinoma and tumor enlargement were evaluated. Tumor enlargement was defined as a ≥25% or 5-mm increase in tumor size. RESULTS: Overall, 121 lesions were analyzed. Within a median observation period of 32.7 months, 5 lesions were diagnosed as carcinomas; the cumulative 5-year incidence of carcinoma was 9.5%. Male sex ( P = 0.046), initial lesion size ≥10 mm ( P = 0.044), and non-pure intestinal phenotype ( P = 0.019) were significantly associated with progression to carcinoma. Tumor enlargement was observed in 22 lesions, with a cumulative 5-year incidence of 33.9%. Initial lesion size ≥10 mm ( P < 0.001), erythematous lesion ( P = 0.002), high-grade adenoma ( P = 0.002), Ki67 negative ( P = 0.007), and non-pure intestinal phenotype ( P = 0.001) were risk factors of tumor enlargement. In a multivariate analysis, an initial lesion size ≥10 mm ( P = 0.010) and non-pure intestinal phenotype ( P = 0.046) were independent and significant risk factors of tumor enlargement. DISCUSSION: Lesion size ≥10 mm and non-pure intestinal phenotype on initial biopsy are risk factors of cancer progression and tumor enlargement in cases with SNDA. Thus, management effectiveness may be improved by focusing on lesion size and the mucinous phenotype.

Enrichment of Immune-Related Genes in Aggressive Primary Breast Angiosarcoma: A Case Report.

Primary breast angiosarcoma is an extremely rare disease with a poor prognosis. Primary angiosarcoma is distinct from secondary angiosarcoma, which usually occurs in patients who have been previously treated for breast cancer. The low incidence of primary breast angiosarcoma has hindered the elucidation of its etiology and potential therapies. Here, we report a case of a patient with primary breast angiosarcoma who experienced recurrence after surgery. The tumor was refractory to systemic treatments, and the patient died 18 months after the surgery. We used RNA sequencing for gene expression profiling of the tumor. A high tumor inflammation signature score indicated enrichment in immune-related signaling. CIBERSORTx, a tool used to characterize the cellular composition of complex tissues based on gene expression, indicated that the immune cells in the tumor were predominantly macrophages, and this was confirmed using immunohistochemical analysis. These findings indicate the possible use of checkpoint immunotherapy for the treatment of primary breast angiosarcoma.

Effects of Flexor Digitorum Longus Muscle Anatomical Structure on the Response to Botulinum Toxin Treatment in Patients with Post-Stroke Claw Foot Deformity.

(1) Background: The purpose of this retrospective case-control study was to determine the relationship between the control of toe movements by flexor hallucis longus (FHL) and flexor digitorum longus (FDL) muscles and the response to treatment with botulinum toxin (BoNT) in post-stroke patients with claw toe. (2) Methods: Subjects with stroke-related leg paralysis/spasticity and claw toes received multiple injections of BoNT (onabotulinumtoxin A) into the FHL or FDL muscles. We investigated the relationship between the mode of transmission of FHL and FDL muscle tension to each toe (MCT) and treatment outcome using the data of 53 patients who received 124 injections with clinically recorded treatment outcome. We also dissected the potential variables that could determine the treatment outcome. (3) Results: The effectiveness of BoNT treatment was significantly altered by FDL-MCT (OR = 0.400, 95% CI = 0.162-0.987, p = 0.047). Analysis of the response to the first BoNT injection showed an odds ratio of FDL-MCT of approximately 6.0 times (OR = 0.168, 95% CI = 0.033-0.857, p = 0.032). The more tibial the influence of the FDL muscle on each toe, the better the treatment outcome on the claw toe. (4) Conclusions: The anatomic relation between FDL muscle and each toe seems to affect the response to treatment with BoNT in post-stroke patients with claw toes.

Transcriptome analysis of human cholangiocytes exposed to carcinogenic 1,2-dichloropropane in the presence of macrophages in vitro.

1,2-Dichloropropane (1,2-DCP), a synthetic organic solvent, has been implicated in causality of cholangiocarcinoma (bile duct cancer). 1,2-DCP-induced occupational cholangiocarcinoma show a different carcinogenic process compared to common cholangiocarcinoma, but its mechanism remains elusive. We reported previously that exposure of MMNK-1 cholangiocytes co-cultured with THP-1 macrophages, but not monocultured MMNK-1 cholangiocytes, to 1,2-DCP induced activation-induced cytidine deaminase (AID) expression, DNA damage and ROS production. The aim of this study was to identify relevant biological processes or target genes expressed in response to 1,2-DCP, using an in vitro system where cholangiocytes are co-cultured with macrophages. The co-cultured cells were exposed to 1,2-DCP at 0, 0.1 or 0.4 mM for 24 h, and then the cell lysates were assessed by transcriptome analysis. 1,2-DCP upregulated the expression of base excision repair genes in MMNK-1 cholangiocytes in the co-cultures, whereas it upregulated the expression of cell cycle-related genes in THP-1 macrophages. Activation of the base excision repair pathway might result from the previously observed DNA damage in MMNK-1 cholangiocytes co-cultured with THP-1 macrophages, although involvement of other mechanisms such as DNA replication, cell death or other types of DNA repair was not disproved. Cross talk interactions between cholangiocytes and macrophages leading to DNA damage in the cholangiocytes should be explored.

Elderly onset age is associated with low efficacy of first anti-tumor necrosis factor treatment in patients with inflammatory bowel disease.

The outcomes of patients with elderly onset (EO) inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (TNF) remains uncertain. The present study evaluated the efficacy and safety of anti-TNF treatment for bio-naïve EO-IBD. Elderly patients were defined as those 60 years and older, and further divided into those with EO (Elderly-EO) and those with non-elderly onset (Elderly-NEO). A total of 432 bio-naïve patients were enrolled in this multicenter observational study, comprising 55 with Elderly-EO (12.7%), 25 with Elderly-NEO (5.8%), and 352 under age 60 (Non-elderly, 81.5%). After 52 weeks of anti-TNF treatment, clinical and steroid-free remission rates were significantly lower in Elderly-EO than in Non-elderly (37.7% and 60.8%; P = 0.001, and 35.9% and 57.8%; P = 0.003, respectively), and comparable between Elderly-NEO and Non-elderly. Multivariate analysis revealed that elderly onset was a significant factor for both clinical remission (OR, 0.49, 95% CI 0.25-0.96) and steroid-free remission (OR, 0.51, 95% CI 0.26-0.99) after 52 weeks of anti-TNF treatment. The rate of cumulative severe adverse events was significantly higher in Elderly-EO than in Non-elderly (P = 0.007), and comparable between Elderly-NEO and Non-elderly. In conclusion, anti-TNF treatment for bio-naïve EO-IBD may be less effective and raise safety concerns.

Claw Toe: Anatomic Guide for Injection of Botulinum Toxin into Foot Muscles.

BACKGROUND: Poor response to injection of botulinum toxin (BoNT) into the flexor digitorum longus (FDL) muscle has been reported especially in patients with claw foot deformity. We previously advocated BoNT injection into the flexor hallucis longus (FHL) muscle in such patients. Here, we determined the functional and anatomical relationships between FHL and FDL. METHODS: Toe flexion pattern was observed during electrical stimulation of FHL and FDL muscles in 31 post-stroke patients with claw-foot deformity treated with BoNT. The FHL and FDL tendon arrangement was also studied in five limbs of three cadavers. RESULTS: Electrical stimulation of the FHL muscle elicited big toe flexion in all 28 cases examined and second toe in 25, but the response was limited to the big toe in 3. FDL muscle stimulation in 29 patients elicited weak big toe flexion in 1 and flexion of four toes (2nd to 5th) in 16 patients. Cadaver studies showed division of the FHL tendon with branches fusing with the FDL tendon in all five limbs examined; none of the tendons was inserted only in the first toe. No branches of the FDL tendon merged with the FHL tendon. CONCLUSION: Our results showed coupling of FHL and FDL tendons in most subjects. Movements of the second and third toes are controlled by both the FDL and FHL muscles. The findings highlight the need for BoNT injection in both the FDL and FHL muscles for the treatment of claw-toe deformity.

Assessment of central aponeurosis curvature as an index of rectus femoris muscle overstrain in individuals with knee osteoarthritis.

BACKGROUND: In medial knee osteoarthritis (knee OA), compensatory overstrain of the rectus femoris (RF) muscle leads to its hypertrophy. We hypothesize that besides hypertrophy of the RF, a prominent flattening of the central aponeurosis (CA) curvature is also indicative of RF. This study aims to evaluate the structural changes in the CA and clarify the conditions associated with RF overstrain in knee OA. OBJECTIVE: Twenty-three legs of 20 elderly without knee OA (elderly group) and 26 legs of 20 individuals with K-L grade II knee OA (knee OA group) with typical "comma"-shaped CA participated in this study. METHODS: The knee extension torque (Nm/kg) in the sitting position, the thickness of the RF and vastus intermedius (VI) muscles (VI), and change in CA curvature (%Curvature) were measured at the mid-thigh by ultrasonography. RESULTS: The knee extension torque was not significantly different between the two groups. Compared to the elderly group, the knee OA group had significantly thicker RF at rest, while the VI thickness during contraction was significantly smaller. The %Curvature was significantly higher in the knee OA group than in the elderly group. CONCLUSIONS: In the knee OA group, the RF was hypertrophic with a more pronounced CA flattening during muscle contraction, although the other quadriceps muscles were atrophic, suggesting an overstrained RF. Assessing thickness and CA curvature of the RF is, therefore, useful and simple for evaluating overstrain caused by RF compensation.

X-ray Diffraction Analysis to Explore Molecular Traces of Eccentric Contraction on Rat Skeletal Muscle Parallelly Evaluated with Signal Protein Phosphorylation Levels.

We performed X-ray diffraction analyses on rat plantaris muscle to determine if there are strain-specific structural changes at the molecular level after eccentric contraction (ECC). ECC was elicited in situ by supramaximal electrical stimulation through the tibial nerve. One hour after a series of ECC sessions, the structural changes that remained in the sarcomere were evaluated using X-ray diffraction. Proteins involved in cell signaling pathways in the muscle were also examined. ECC elicited by 100, 75, and 50 Hz stimulation respectively developed peak tension of 1.34, 1.12 and 0.79 times the isometric maximal tetanus tension. The series of ECC sessions phosphorylated the forkhead box O proteins (FoxO) in a tension-time integral-dependent manner, as well as phosphorylated the mitogen-activated protein kinases (MAPK) and a protein in the mammalian target of rapamycin (mTOR) pathway in a maximal tension dependent manner. Compared to isometric contractions, ECC was more efficient in phosphorylating the signaling proteins. X-ray diffraction revealed that the myofilament lattice was preserved even after intense ECC stimulation at 100 Hz. Additionally, ECC < 75 Hz preserved the molecular alignment of myoproteins along the myofilaments, while 75-Hz stimulation induced a slight but significant decrease in the intensity of meridional troponin reflection at 1/38 nm-1, and of myosin reflection at 1/14.4 nm-1. These two reflections demonstrated no appreciable decrease with triple repetitions of the standard series of ECC sessions at 50 Hz, suggesting that the intensity decrease depended on the instantaneous maximal tension development rather than the total load of contraction, and was more likely linked with the phosphorylation of MAPK and mTOR signaling proteins.

Vascular endothelial growth factor-A is an Immunohistochemical biomarker for the efficacy of bevacizumab-containing chemotherapy for duodenal and jejunal adenocarcinoma.

BACKGROUND: The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. METHODS: This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, ß-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. RESULTS: A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30-0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. CONCLUSION: Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.

Role of Macrophages in Cytotoxicity, Reactive Oxygen Species Production and DNA Damage in 1,2-Dichloropropane-Exposed Human Cholangiocytes In Vitro.

1,2-Dichloropropane (1,2-DCP), a synthetic chlorinated organic compound, was extensively used in the past in offset color proof-printing. In 2014, the International Agency for Research on Cancer (IARC) reclassified 1,2-DCP from its initial Group 3 to Group 1. Prior to the reclassification, cholangiocarcinoma was diagnosed in a group of workers exposed to 1,2 -DCP in an offset color proof-printing company in Japan. In comparison with other forms of cholangiocarcinoma, 1,2-DCP-induced cholangiocarcinoma was of early onset and accompanied by extensive pre-cancerous lesions in large bile ducts. However, the mechanism of 1,2-DCP-induced cholangiocarcinoma is poorly understood. Inflammatory cell proliferation was observed in various sites of the bile duct in the noncancerous hepatic tissues of the 1,2-DCP-induced cholangiocarcinoma. The aim of this study was to enhance our understanding of the mechanism of 1,2-DCP-related cholangiocarcinogenesis. We applied an in vitro system to investigate the effects of 1,2-DCP, using MMNK-1 cholangiocytes cultured alone or with THP-1 macrophages. The cultured cells were exposed to 1,2-DCP at 0, 0.1, 0.2, 0.4, and 0.8 mM for 24 h, and then assessed for cell proliferation, cell cytotoxicity, DNA damage, and ROS production. Exposure to 1,2-DCP increased proliferation of MMNK-1 cholangiocytes cultured alone, but not those cultured with macrophages. 1,2-DCP also increased LDH cytotoxicity, DNA damage, and ROS production in MMNK-1 cholangiocytes co-cultured with macrophages but not those cultured alone. 1,2-DCP increased TNFα and IL-1ß protein expression in macrophages. The results highlight the role of macrophages in enhancing the effects of 1,2-DCP on cytotoxicity, ROS production, and DNA damage in cholangiocytes.

1,2-Dichloropropane induces γ-H2AX expression in human cholangiocytes only in the presence of macrophages.

Recent epidemiological studies reported cases of cholangiocarcinoma in workers exposed to 1,2-dichloropropane (1,2-DCP) in an offset proof printing factory in Japan. The present study investigated the effects of 1,2-DCP on the expression of histone family member X (H2AX) phosphorylated on Ser 139 (γ-H2AX), a marker of DNA double strand break, in human immortalized cholangiocytes MMNK-1 cells. Mono-cultures of MMNK-1 cells and co-cultures of MMNK-1 cells with THP-1 macrophages were exposed to 1,2-DCP at concentrations of 100 and 500 µM for 24 h. Expression of γ-H2AX was visualized by immunofluorescence staining. Exposure to 1,2-DCP had no effect on the expression of γ-H2AX in mono-cultured MMNK-1 cells, but significantly increased the number of nuclear foci stained by γ-H2AX in MMNK-1 cells co-cultured with THP-1 macrophages. Exposure to 1,2-DCP also significantly increased the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in co-cultured MMNK-1 cells. The results suggest that macrophages play a critical role by producing cytokines in 1,2-DCP-induced DNA double strand break in MMNK-1 cells.

Stepwise generation of AID knock-in and conditional knockout mice from a single gene-targeting event.

Activation-induced cytidine deaminase (AID) encoded by the Aicda gene initiates class-switch recombination and somatic hypermutation of immunoglobulin genes. In addition to this function, AID is also implicated in the epigenetic regulation in pluripotent stem cells and in the oncogenesis of lymphoid and non-lymphoid origins. To examine AID's role in specific cell types, we developed mouse strains of conditional knockout (Aicda-FL) and knock-in with a red fluorescent protein gene (RFP) inserted into the Aicda locus (Aicda-RFP). These two strains were obtained from a single targeting event in embryonic stem cells by a three-loxP or tri-lox strategy. Partial and complete recombination among the three loxP sites in the Aicda-RFP locus gave rise to Aicda-FL and AID-deficient loci (Aicda-KO), respectively, after mating Aicda-RFP mice with Cre-expressing mice driven by tissue-non-specific alkaline phosphate promoter. We confirmed RFP expression in B cells of germinal centers of intestine-associated lymphoid tissue. Mice homozygous for each allele were obtained and were checked for AID activity by class-switch and hypermutation assays. AID activity was normal for Aicda-FL but partially and completely absent for Aicda-RFP and Aicda-KO, respectively. Aicda-FL and Aicda-RFP mice would be useful for studying AID function in subpopulations of B cells and in non-lymphoid cells.

Prophylactic clipping not effective in preventing post-polypectomy bleeding for < 20-mm colon polyps: A multicenter, open-label, randomized controlled trial.

BACKGROUND AND AIM: Prophylactic clipping (PC) after polypectomy has the potential to prevent post-polypectomy bleeding (PPB). We aimed to evaluate the effectiveness of PC in preventing PPB for < 20-mm polyps. METHODS: This multicenter, open-label, randomized controlled trial conducted from December 2013 to June 2017 at 10 institutions randomly assigned 1080 patients with < 20-mm colon polyps to the non-PC and PC groups. Allocation factors were institution, antiplatelet drug use, and polyp number. The primary endpoint was differences in PPB rates between the groups. The severity of PPB and post-procedural abdominal symptoms were also investigated. These endpoints in intention-to-treat and per-protocol (PP) analyses were evaluated. RESULTS: We investigated 1039 patients with 2960 lesions. There was no significant difference between the groups in characteristics including age, sex, hypertension, diabetes, hyperlipidemia, antiplatelet drug use, and lesion characteristics such as type and size. Excluding the clip used in the non-PC group, intraoperative bleeding, and deviation of protocol, 903 patients were investigated in PP analysis. There was no significant difference in the PPB rate between the non-PC and PC groups (2.7% vs 2.3%, P = 0.6973 [intention-to-treat analysis]; 3.0 vs 2.4%, P = 0.7353 [PP analysis]). Severe PPB (≥ grade 3) was similar between the groups. Total procedure time was significantly shorter in the non-PC group than in the PC group (31 vs 36 min, P = 0.0002). Post-procedural abdominal fullness was less common in the non-PC group than in the PC group (20.8% vs 25.6%, P = 0.0833). CONCLUSION: Prophylactic clipping is not effective in preventing PBB for < 20-mm colon polyps (UMIN000012163).

Comparison of performances of artificial intelligence versus expert endoscopists for real-time assisted diagnosis of esophageal squamous cell carcinoma (with video).

BACKGROUND AND AIMS: Narrow-band imaging (NBI) is currently regarded as the standard modality for diagnosing esophageal squamous cell carcinoma (SCC). We developed a computerized image-analysis system for diagnosing esophageal SCC by NBI and estimated its performance with video images. METHODS: Altogether, 23,746 images from 1544 pathologically proven superficial esophageal SCCs and 4587 images from 458 noncancerous and normal tissue were used to construct an artificial intelligence (AI) system. Five- to 9-second video clips from 144 patients captured by NBI or blue-light imaging were used as the validation dataset. These video images were diagnosed by the AI system and 13 board-certified specialists (experts). RESULTS: The diagnostic process was divided into 2 parts: detection (identify suspicious lesions) and characterization (differentiate cancer from noncancer). The sensitivities, specificities, and accuracies for the detection of SCC were, respectively, 91%, 51%, and 63% for the AI system and 79%, 72%, and 75% for the experts. The sensitivity of the AI system was significantly higher than that of the experts, but its specificity was significantly lower. Sensitivities, specificities, and accuracy for the characterization of SCC were, respectively, 86%, 89%, and 88% for the AI system and 74%, 76%, and 75% for the experts. The receiver operating characteristic curve showed that the AI system had significantly better diagnostic performance than the experts. CONCLUSIONS: Our AI system showed significantly higher sensitivity for detecting SCC and higher accuracy for characterizing SCC from noncancerous tissue than endoscopic experts.

Psychologic stress and disease activity in patients with inflammatory bowel disease: A multicenter cross-sectional study.

BACKGROUND AND AIMS: Psychologic stress can affect the pathogenesis of inflammatory bowel disease (IBD), but the precise contribution of psychologic stress to IBD remains unclear. We investigated the association of psychologic stress with disease activity in patients with IBD, especially in terms of mental state and sleep condition. METHODS: This was a multi-center observational study comprising 20 institutions. Data were collected using survey forms for doctors and questionnaires for patients, and the association of psychologic stress with clinical parameters was investigated. Mental state was evaluated using the Center for Epidemiologic Studies Depression (CES-D) scale, and sleep condition was evaluated by querying patients about the severity of insomnia symptoms. RESULTS: A total of 1078 IBD patients were enrolled, including 303 patients with Crohn's disease and 775 patients with ulcerative colitis. Seventy-five percent of IBD patients believed that psychologic stress triggered an exacerbation of their disease (PSTE group) and 25% did not (non-PSTE group). The CES-D scores were significantly higher for patients with clinically active disease than for those in remission in the PSTE group (median (interquartile range) = 7 (4-9.5) vs. 5 (3-7), p < .0001), but not in the non-PSTE group (5 (2-8) vs. 4 (3-7), p = 0.78). Female sex and disease exacerbation by factors other than psychologic stress were independent factors of psychologic stress-triggered disease exacerbation. Also, patients with insomnia had higher disease activity than those without insomnia, especially in the PSTE group. CONCLUSIONS: A worsened mental state correlates with disease activity in IBD patients, especially those who believe that their disease is exacerbated by psychologic stress.

Efficacy of vonoprazan for the prevention of bleeding after gastric endoscopic submucosal dissection with continuous use of antiplatelet agents.

Background Post-procedural bleeding, after gastric endoscopic submucosal dissection (ESD) for high risk thromboembolic cases that require continuous antiplatelet therapy, is challenging. Its incidence rate is > 20 % among those using conventional antacids. We evaluated the efficacy of perioperative management with vonoprazan to prevent post-ESD bleeding. Materials and methods This was a multicenter prospective interventional trial conducted at 10 Japanese referral centers. Patients who regularly used antiplatelet agents (aspirin or thienopyridine derivatives, etc.) and who required continuous antithrombotic medication due to high thromboembolic risk were enrolled. They underwent gastric ESD with continuous aspirin therapy. Oral administration of vonoprazan (20 mg daily) was started from the day of ESD and continued for 28 days. The primary end point was the incidence of post-ESD bleeding. The sample size was 50 patients, and vonoprazan was considered to be effective when the upper threshold of the 95 % confidence interval (CI) for post-ESD bleeding did not exceed 20 %. Results Although 50 patients were enrolled, one patient withdrew consent. Therefore, 49 patients were included in the analysis. One patient who used aspirin and clopidogrel experienced bleeding 11 days after ESD. The overall post-ESD bleeding rate was 2.0 % (1/49; 95 %CI 0.4-10.7 %). Thromboembolic events were not observed. One case of ESD-associated adverse events (perforation) and one case of drug-associated adverse events (drug eruption, possibly due to vonoprazan) were observed. Conclusions Vonoprazan may be efficacious for preventing post-ESD bleeding in patients using continuous antiplatelet therapy, warranting further comparative study to definitively test the effectiveness of the drug.

Spatiotemporally Dependent Vascularization Is Differently Utilized among Neural Progenitor Subtypes during Neocortical Development.

To facilitate efficient oxygen and nutrient delivery, blood vessels in the brain form three-dimensional patterns. However, little is known about how blood vessels develop stereographically in the neocortex and how they control the expansion and differentiation of neural progenitors during neocortical development. We show that highly vascularized and avascular regions are strictly controlled in a spatially and temporally restricted manner and are associated with distinct cell populations. Dividing basal progenitors and oligodendrocyte precursors preferentially contact honeycomb vessels, but dividing apical progenitors are localized in avascular regions without Flt1-positive endothelial cells but directly contact with sprouting neovascular tip cells. Therefore, not all blood vessels are associated equally with neural progenitors. Furthermore, a disruption of normal vascular patterning can induce abnormalities in neural development, whereas the impaired features of neural progenitors influenced angiogenesis patterning. These results indicate that close association between the nervous and vascular systems is essential for neocortex assembly.

Alignment of the rearfoot and foot pressure patterns of individuals with medial tibial stress syndrome: A cross-sectional study.

OBJECTIVE: To compare the rearfoot alignment (leg-heel angle, LHA) during standing and walking, and foot pressure during walking between individuals with medial tibial stress syndrome (MTSS) and asymptomatic individuals participating in daily sports. DESIGN: A cross-sectional study. SETTING: Research laboratory. PARTICIPANTS: MTSS (18 legs) and control (15 legs) participants. MAIN OUTCOME MEASURES: The LHA in the frontal plane during walking and standing; partial foot pressures expressed as the percentage of body weight (%PFP); and transverse width of the center of pressure (COP) path expressed as the percentage of foot width (%Trans) on walking. RESULTS: The LHA while walking was significantly higher in MTSS individuals, whereas the LHA while standing was not significantly different. The %PFPs of medial metatarsal areas were significantly higher in MTSS patients, whereas the %Trans was significantly lower. CONCLUSIONS: In individuals with MTSS, the LHA is similar to controls while standing but higher (more everted) while walking while there is higher pressure under the medial metatarsal areas and the COP is more medial. Rearfoot malalignment in individuals with mild to moderate MTSS can be detected on walking, even if the alignment on standing is normal.

In Vivo Flattening of the Central Aponeurosis of the Rectus Femoris Due to Knee Extension Torque in Healthy Young and Elderly Individuals With Knee Osteoarthritis.

ABSTRACT: We aimed to elucidate the relationship between active force production and the curvature of the central aponeurosis (CA) of the rectus femoris in young healthy participants as fundamental data and compare the muscle CA curvature before and after straight leg raising (SLR) training in participants with knee osteoarthritis (OA). Central aponeurosis curvature was determined during submaximal and maximal voluntary contractions (MVCs) using ultrasonography. Twenty-five young healthy female volunteers underwent ultrasonographic measurements under conditions of isometric MVC. They were divided into a flat shaped CA group (flat) and an incompletely flat shaped CA group (remnant). Central aponeurosis curvature was calculated as the ratio of CA height and length in the axial view. Central aponeurosis shape and muscular strength before and after muscle training were measured in 11 participants with knee OA. In the young healthy individuals, maximal voluntary torque and changes in CA curvature were significantly higher in the flat group than in the remnant group (2.15 Nm/kg and - 17.7% vs 1.75 Nm/kg and -9.8%, respectively; P = 0.005). The rate of change of the CA curvature during contraction was significantly correlated with maximal voluntary torque corrected for body mass (r = 0.512). The CA curvature progressively decreased as %MVC increased. In the OA group, CA curvature during MVC after SLR training was significantly lower than that before SLR training (3.2% vs 7.2%; P = 0.031). Central aponeurosis curvature was associated with muscle strength, and the results supported our hypothesis that geometric observation of CA changes during contractions may reflect muscle fiber function. We aim to develop a new ultrasonographic skeletal muscle evaluation method based on our present findings.

Exposure to 1,2-Dichloropropane Upregulates the Expression of Activation-Induced Cytidine Deaminase (AID) in Human Cholangiocytes Co-Cultured With Macrophages.

1,2-dichloropropane (1,2-DCP) was reclassified recently by IARC as a Group 1 carcinogen based on epidemiological studies on an outbreak of cholangiocarcinoma in offset-printing workers exposed to 1,2-DCP in Japan. However, the underlying mechanism of 1,2-DCP-induced cholangiocarcinoma remains obscure. A previous whole-genome mutation analysis of cholangiocarcinoma of 4 cases exposed to 1,2-DCP suggested the involvement of activation-induced cytidine deaminase (AID), based on specific signatures of mutation patterns. The objective of the present study is to determine whether exposure to 1,2-DCP induces expression of AID in human cholangiocytes. Human MMNK-1 cholangiocytes, differentiated THP-1 macrophages, and co-cultures of MMNK-1/THP-1 cells were exposed to 1,2-DCP at different concentrations and time intervals. The mRNA expression levels of AID and related genes were quantified by real-time PCR. Protein expression was measured by immunostaining. Alkaline Comet assay was performed to examine DNA damage. The results showed that 1,2-DCP alone did not change AID expression in MMNK-1 cholangiocytes. 1,2-DCP significantly increased pro-inflammatory cytokine TNF-α expression in THP-1 macrophages. TNF-α treatment upregulated expression of AID, NF-κB, and IκB in MMNK-1 cholangiocytes. SN50, a NF-κB inhibitor, significantly downregulated TNF-α-induced AID expression, suggesting the involvement of NF-κB pathway in TNF-α-induced AID expression. Exposure to 1,2-DCP significantly increased AID expression in MMNK-1 cholangiocytes co-cultured with THP-1 macrophages. Comet assay showed that 1,2-DCP-induced DNA damage in MMNK-1 cholangiocytes, as indicated by increased tail DNA% and tail moment, was enhanced when co-cultured with macrophages. The results suggest that inflammatory response of macrophages and consequent aberrant AID expression or DNA damage in the cholangiocytes underlie the mechanism of 1,2-DCP-induced cholangiocarcinoma in humans.