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Background: For the treatment of coronoid process fractures, medial, lateral, anterior, anteromedial, and posterior approaches have been increasingly reported; however, there is no general consensus on the method of fixation of coronal fractures. Here, we present a highly-extensile minimally invasive approach to treat coronoid process fractures using a mini-plate that can achieve anatomic reduction, stable fixation, and anterior capsular repair. Further, the study aimed to determine the complication rate of the anterior minimally invasive approach and to evaluate functional and clinical patient-reported outcomes during follow-up., Methods: Thirty-one patients diagnosed with coronoid fractures accompanied with a "terrible triad" or posteromedial rotational instability between April 2012 and October 2018 were included in the analysis. Anatomical reduction and mini-plate fixation of coronoid fractures were performed using an anterior minimally invasive approach. Patient-reported outcomes were evaluated using the Mayo Elbow Performance Index (MEPI) score, range of motion (ROM), and the visual analog score (VAS). The time of fracture healing and complications were recorded., Results: The mean follow-up time was 26.7 months (range, 14-60 months). The average time to radiological union was 3.6 ± 1.3 months. During the follow-up period, the average elbow extension was 6.8 ± 2.9° while the average flexion was 129.6 ± 4.6°. According to Morrey's criteria, 26 (81%) elbows achieved a normal desired ROM. At the last follow-up, the mean MEPI score was 98 ± 3.3 points. There were no instances of elbow instability, elbow joint stiffness, subluxation or dislocation, infection, blood vessel complications, or nerve palsy. Overall, 10 elbows (31%) experienced heterotopic ossification., Conclusion: An anterior minimally invasive approach allows satisfactory fixation of coronoid fractures while reducing incision complications due to over-dissection of soft tissue injuries. In addition, this incision does not compromise the soft tissue stability of the elbow joint and allows the patient a more rapid return to rehabilitation exercises., (© 2024. The Author(s).)

Gastric organoids are models created in the laboratory using stem cells and sophisticated three-dimensional cell culture techniques. These models have shown great promise in providing valuable insights into gastric physiology and advanced disease research. This review comprehensively summarizes and analyzes the research advances in culture methods and techniques for adult stem cells and induced pluripotent stem cell-derived organoids, and patient-derived organoids. The potential value of gastric organoids in studying the pathogenesis of stomach-related diseases and facilitating drug screening is initially discussed. The construction of gastric organoids involves several key steps, including cell extraction and culture, three-dimensional structure formation, and functional expression. Simulating the structure and function of the human stomach by disease modeling with gastric organoids provides a platform to study the mechanism of gastric cancer induction by Helicobacter pylori . In addition, in drug screening and development, gastric organoids can be used as a key tool to evaluate drug efficacy and toxicity in preclinical trials. They can also be used for precision medicine according to the specific conditions of patients with gastric cancer, to assess drug resistance, and to predict the possibility of adverse reactions. However, despite the impressive progress in the field of gastric organoids, there are still many unknowns that need to be addressed, especially in the field of regenerative medicine. Meanwhile, the reproducibility and consistency of organoid cultures are major challenges that must be overcome. These challenges have had a significant impact on the development of gastric organoids. Nonetheless, as technology continues to advance, we can foresee more comprehensive research in the construction of gastric organoids. Such research will provide better solutions for the treatment of stomach-related diseases and personalized medicine., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Our experience with the surgical flip-dislocation of the bicolumnar (SFDB) approach for type AO 13C3 humeral fractures indicates that this surgical approach can be performed safely and effectively in appropriately selected patients. We aimed to evaluate the clinical outcomes of the SFDB approach without olecranon osteotomy (OO) for type AO 13C3 distal humeral fractures., Methods: We retrospectively reviewed 65 cases of type AO 13C3 distal humeral fractures treated between April 2008 and July 2018; 33 patients were treated with the SFDB approach, and the remaining were treated with OO. Propensity score matching was used to control for sex, age, and the American Society of Anesthesiology score. Elbow pain, range of motion, stability, and function were assessed using the Mayo Elbow Performance Index (MEPI) and the Disabilities of the Arm, Shoulder, and Hand questionnaire. Clinical complications, reoperation rates, and radiographic results were compared between the groups., Results: Operative time and blood loss were significantly lower in the SFDB group than in the OO group (P = 0.001, P = 0.002, respectively). At the final follow-up, the mean postoperative MEPI did not significantly differ between the groups (P = 0.628). According to Morrey's criteria, a typical functional range of elbow motion was achieved in 12 and 15 patients in the SFDB and OO groups, respectively., Conclusions: The SFDB approach achieves superior exposure of the articular surface without injury to the extensor mechanism in type 13C3 articular surface fracture treatment. This approach also results in good early functional recovery and clinical outcomes, with a low risk of complications., (© 2023. The Author(s).)

Developed in early 1980s, transarterial chemoembolization (TACE) with Lipiodol was adopted globally after large-scale randomized control trials and meta-analyses proving its effectiveness were completed. Also known as "conventional TACE" (cTACE), TACE is currently the first-line treatment for patients with unresectable intermediate stage hepatocellular carcinoma (HCC) and delivers both ischemic and cytotoxic effects to targeted tumors. Although new technology and clinical studies have contributed to a more comprehensive understanding of when and how to apply this widely-adopted therapeutic modality, some of these new findings and techniques have yet to be incorporated into a guideline appropriate for Taiwan. In addition, differences in the underlying liver pathologies and treatment practices for transcatheter embolization between Taiwan and other Asian or Western populations have not been adequately addressed, with significant variations in the cTACE protocols adopted in different parts of the world. These mainly revolve around the amount and type of chemotherapeutic agents used, the type of embolic materials, reliance on Lipiodol, and the degree of selectiveness in catheter positioning. Subsequently, interpreting and comparing results obtained from different centers in a systematic fashion remain difficult, even for experienced practitioners. To address these concerns, we convened a panel of experts specializing in different aspects of HCC treatment to devise modernized recommendations that reflect recent clinical experiences, as well as cTACE protocols which are tailored for use in Taiwan. The conclusions of this expert panel are described herein., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chang, Lee, Liang, Liu, Chuang, Wu, Cheng, Huang, Tseng, Hung, Wu, Chern, Cheng, Wu, Cheng, Chiang and Liang.)

Aims: The incremental usefulness of circulating biomarkers from different pathological pathways for predicting mortality has not been evaluated in acute Type A aortic dissection (ATAAD) patients. We aim to develop a risk prediction model and investigate the impact of arch repair strategy on mortality based on distinct risk stratifications., Methods and Results: A total of 3771 ATAAD patients who underwent aortic surgery retrospectively included were randomly divided into training and testing cohorts at a ratio of 7:3 for the development and validation of the risk model based on multiple circulating biomarkers and conventional clinical factors. Extreme gradient boosting was used to generate the risk models. Subgroup analyses were performed by risk stratifications (low vs. middle-high risk) and arch repair strategies (proximal vs. extensive arch repair). Addition of multiple biomarkers to a model with conventional factors fitted an ABC risk model consisting of platelet-leucocyte ratio, mean arterial pressure, albumin, age, creatinine, creatine kinase-MB, haemoglobin, lactate, left ventricular end-diastolic dimension, urea nitrogen, and aspartate aminotransferase, with adequate discrimination ability {area under the receiver operating characteristic curve (AUROC): 0.930 [95% confidence interval (CI) 0.906-0.954] and 0.954, 95% CI (0.930-0.977) in the derivation and validation cohort, respectively}. Compared with proximal arch repair, the extensive repair was associated with similar mortality risk among patients at low risk [odds ratio (OR) 1.838, 95% CI (0.559-6.038); P = 0.316], but associated with higher mortality risk among patients at middle-high risk [OR 2.007, 95% CI (1.460-2.757); P < 0.0001]., Conclusion: In ATAAD patients, the simultaneous addition of circulating biomarkers of inflammatory, cardiac, hepatic, renal, and metabolic abnormalities substantially improved risk stratification and individualized arch repair strategy., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Otolith organs of the inner ear are innervated by two parallel afferent projections to the brainstem and cerebellum. These innervations were proposed to segregate across the line of polarity reversal (LPR) within each otolith organ, which divides the organ into two regions of hair cells (HC) with opposite stereociliary orientation. The relationship and functional significance of these anatomical features are not known. Here, we show regional expression of Emx2 in otolith organs, which establishes LPR, mediates the neuronal segregation across LPR and constitutes the bidirectional sensitivity function. Conditional knockout (cKO) of Emx2 in HCs lacks LPR. Tmie cKO, in which mechanotransduction was abolished selectively in HCs within the Emx2 expression domain also lacks bidirectional sensitivity. Analyses of both mutants indicate that LPR is specifically required for mice to swim comfortably and to traverse a balance beam efficiently, but LPR is not required for mice to stay on a rotating rod., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: To develop an inflammation-based risk stratification tool for operative mortality in patients with acute type A aortic dissection., Methods: Between January 1, 2016 and December 31, 2021, 3124 patients from Beijing Anzhen Hospital were included for derivation, 571 patients from the same hospital were included for internal validation, and 1319 patients from other 12 hospitals were included for external validation. The primary outcome was operative mortality according to the Society of Thoracic Surgeons criteria. Least absolute shrinkage and selection operator regression were used to identify clinical risk factors. A model was developed using different machine learning algorithms. The performance of the model was determined using the area under the receiver operating characteristic curve (AUC) for discrimination, calibration curves, and Brier score for calibration. The final model (5A score) was tested with respect to the existing clinical scores., Results: Extreme gradient boosting was selected for model training (5A score) using 12 variables for prediction-the ratio of platelet to leukocyte count, creatinine level, age, hemoglobin level, prior cardiac surgery, extent of dissection extension, cerebral perfusion, aortic regurgitation, sex, pericardial effusion, shock, and coronary perfusion-which yields the highest AUC (0.873 [95% confidence interval (CI) 0.845-0.901]). The AUC of 5A score was 0.875 (95% CI 0.814-0.936), 0.845 (95% CI 0.811-0.878), and 0.852 (95% CI 0.821-0.883) in the internal, external, and total cohort, respectively, which outperformed the best existing risk score (German Registry for Acute Type A Aortic Dissection score AUC 0.709 [95% CI 0.669-0.749])., Conclusion: The 5A score is a novel, internally and externally validated inflammation-based tool for risk stratification of patients before surgical repair, potentially advancing individualized treatment., Trial Registration: clinicaltrials.gov Identifier: NCT04918108., (© 2022 The Authors.)

Diarrhoea is a common clinical condition; its pathogenesis is strongly associated with gut microbiota dysbiosis. Limonitum is a well-known traditional Chinese medicine that exerts appreciable benefits regarding the amelioration of diarrhoea. However, the mechanism through which Limonitum ameliorates diarrhoea remains unclear. Here, the efficacy and underlying mechanism of Limonitum decoction (LD) regarding diarrhoea were explored from the aspect of gut microbiota. Castor oil (CO) was used to induce diarrhoea in mice, which were then used to evaluate the effects of LD regarding the timing of the first defecation, diarrhoea stool rate, degree of diarrhoea, diarrhoea score, intestinal propulsive rate, and weight of intestinal contents. The concentrations of short-chain fatty acids (SCFAs), including acetic, propionic, isobutyric, butyric and valeric acids, were analysed by gas chromatography-mass spectrometry (GC-MS). The 16S rRNA high-throughput sequencing technology was applied to evaluate changes in the gut microbiota under exposure to LD. LD was found to effectively ameliorate the symptoms of diarrhoea, and the diversity and relative abundance of gut microbiota were restored to normal levels following LD treatment. Additionally, LD significantly restored the observed reductions in SCFAs. These results provide strong evidence that LD can sufficiently ameliorate diarrhoea in mice by regulating their gut microbiota. The findings presented here highlight that Limonitum may constitute a prospective remedy for diarrhoea.

This study investigated the regulation of GRP78 in tumour-associated macrophage polarization in lung cancer. First, our results showed that GRP78 was upregulated in macrophages during M2 polarization and in a conditioned medium derived from lung cancer cells. Next, we found that knocking down GRP78 in macrophages promoted M1 differentiation and suppressed M2 polarization via the Janus kinase/signal transducer and activator of transcription signalling. Moreover, conditioned medium from GRP78- or insulin-like growth factor 1-knockdown macrophages attenuated the survival, proliferation, and migration of lung cancer cells, while conditioned medium from GRP78-overexpressing macrophages had the opposite effects. Additionally, GRP78 knockdown reduced both the secretion of insulin-like growth factor 1 and the phosphorylation of the insulin-like growth factor 1 receptor. Interestingly, insulin-like growth factor 1 neutralization downregulated GRP78 and suppressed GRP78 overexpression-induced M2 polarization. Mechanistically, insulin-like growth factor 1 treatment induced the translocation of GRP78 to the plasma membrane and promoted its association with the insulin-like growth factor 1 receptor. Finally, IGF-1 blockade and knockdown as well as GRP78 knockdown in macrophages inhibited M2 macrophage-induced survival, proliferation, and migration of lung cancer cells both in vitro and in vivo., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The potential association between appendectomy and non-typhoidal Salmonella (NTS) infection has not been elucidated. We hypothesized that appendectomy may be associated with gut vulnerability to NTS. The data were retrospectively collected from the Taiwan National Health Insurance Research Database to describe the incidence rates of NTS infection requiring hospital admission among patients with and without an appendectomy. A total of 208,585 individuals aged ≥18 years with an appendectomy were enrolled from January 2000 to December 2012, and compared with a control group of 208,585 individuals who had never received an appendectomy matched by propensity score (1:1) by index year, age, sex, occupation, and comorbidities. An appendectomy was defined by the International Classification of Diseases, Ninth Revision, Clinical Modification Procedure Codes . The main outcome was patients who were hospitalized for NTS. Cox proportional hazards models were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). Two sensitivity analyses were conducted for cross-validation. Of the 417,170 participants (215,221 (51.6%) male), 208,585 individuals (50.0%) had an appendectomy, and 112 individuals developed NTS infection requiring hospitalization. In the fully adjusted multivariable Cox proportional hazards regression model, the appendectomy group had an increased risk of NTS infection (adjusted HR (aHR), 1.61; 95% CI, 1.20-2.17). Females and individuals aged 18 to 30 years with a history of appendectomy had a statistically higher risk of NTS than the control group (aHR, 1.92; 95% CI, 1.26-2.93 and aHR, 2.67; 95% CI, 1.41-5.07). In this study, appendectomy was positively associated with subsequent hospitalization for NTS. The mechanism behind this association remains uncertain and needs further studies to clarify the interactions between appendectomy and NTS.

Each hair cell (HC) precursor of zebrafish neuromasts divides to form two daughter HCs of opposite hair bundle orientations. Previously, we showed that transcription factor Emx2, expressed in only one of the daughter HCs, generates this bidirectional HC pattern (Jiang et al., 2017). Here, we asked whether Emx2 mediates this effect by changing location of hair bundle establishment or positions of HCs since daughter HCs are known to switch positions with each other. We showed this HC rearrangement, redefined as two processes named Rock and Roll, is required for positional acquisition of HCs. Apical protrusion formation of nascent HCs and planar polarity signaling are both important for the Rock and Roll. Emx2 facilitates Rock and Roll by delaying apical protrusion of its nascent HCs but it does not determine HCs' ultimate positions, indicating that Emx2 mediates bidirectional HC pattern by changing the location where hair bundle is established in HCs., Competing Interests: SO, YJ, DM No competing interests declared, DW Reviewing editor, eLife

Directional sensitivity of hair cells (HCs) is conferred by the aymmetric apical hair bundle, comprised of a kinocilium and stereocilia staircase. The mother centriole (MC) forms the base of the kinocilium and the stereocilia develop adjacent to it. Previously, we showed that transcription factor Emx2 reverses hair bundle orientation and its expression in the mouse vestibular utricle is restricted, resulting in two regions of opposite bundle orientation (Jiang et al., 2017). Here, we investigated establishment of opposite bundle orientation in embryonic utricles by live-imaging GFP-labeled centrioles in HCs. The daughter centriole invariably migrated ahead of the MC from the center to their respective peripheral locations in HCs. Comparing HCs between utricular regions, centriole trajectories were similar but they migrated toward opposite directions, suggesting that Emx2 pre-patterned HCs prior to centriole migration. Ectopic Emx2 , however, reversed centriole trajectory within hours during a critical time-window when centriole trajectory was responsive to Emx2., Competing Interests: YT No competing interests declared, DW Reviewing editor, eLife

Retinoic acid (RA), a vitamin A (retinol) derivative, has pleiotropic functions during embryonic development. The synthesis of RA requires two enzymatic reactions: oxidation of retinol into retinaldehyde by alcohol dehydrogenases (ADHs) or retinol dehydrogenases (RDHs); and oxidation of retinaldehyde into RA by aldehyde dehydrogenases family 1, subfamily A (ALDH1as), such as ALDH1a1, ALDH1a2 and ALDH1a3. Levels of RA in tissues are regulated by spatiotemporal expression patterns of genes encoding RA-synthesizing and -degrading enzymes, such as cytochrome P450 26 (Cyp26 genes). Here, we show that RDH10 is important for both sensory and non-sensory formation of the vestibule of the inner ear. Mice deficient in Rdh10 exhibit failure of utricle-saccule separation, otoconial formation and zonal patterning of vestibular sensory organs. These phenotypes are similar to those of Aldh1a3 knockouts, and the sensory phenotype is complementary to that of Cyp26b1 knockouts. Together, these results demonstrate that RDH10 and ALDH1a3 are the key RA-synthesis enzymes involved in vestibular development. Furthermore, we discovered that RA induces Cyp26b1 expression in the developing vestibular sensory organs, which generates the differential RA signaling required for zonal patterning., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

The purpose of this study was to evaluate the deep vein thrombosis (DVT) and pulmonary embolism (PE) risk among patients with a diagnosis of nontyphoidal salmonellosis (NTS) in an Asian population. The risk was analyzed in a cohort of 17,855 patients newly diagnosed with NTS and 71,420 individuals without NTS using a hospitalization claim dataset. Both groups were matched by age, sex, and index date as an original analysis. A Cox proportional-hazards regression model was applied to estimate the risk of DVT and PE, accounting for any competing event (death). With a follow-up of 4.94 (±3.93) years in the NTS group and 6.30 (±3.67) years in the non-NTS group, the adjusted subhazard ratios (SHRs) of DVT and PE were 1.83 (95% CI 1.44-2.31) and 1.84 (95% CI 1.30-2.60). The NTS group had an increased risk of DVT and PE compared with the control group in all of the age subgroups. Stratified analyses showed that patients aged 18-39 years in the NTS group had significantly higher DVT and PE risks compared with patients of the same age in the non-NTS group (aHR, 5.95; 95% CI, 2.22-15.91 for DVT; aHR 6.72; 95% CI, 2.23-20.30 for PE). The P -value for interaction between age and exposure of NTS is <0.001 for DVT and 0.004 for PE in our sub-group analyses. The findings were cross-validated by a re-analysis with propensity score matching (PSM), and that revealed consistent results. Despite of low absolute risk, clinicians should be aware that patients with an NTS hospitalization history is at increased risk for VTE especially when assessing patients coincident with other VTE risk factors., Competing Interests: The authors declare that there is no conflict of interest.

Each vestibular sensory epithelium in the inner ear is divided morphologically and physiologically into two zones, called the striola and extrastriola in otolith organ maculae, and the central and peripheral zones in semicircular canal cristae. We found that formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)-mediated degradation of retinoic acid (RA). In Cyp26b1 conditional knockout mice, formation of striolar/central zones is compromised, such that they resemble extrastriolar/peripheral zones in multiple features. Mutants have deficient vestibular evoked potential (VsEP) responses to jerk stimuli, head tremor and deficits in balance beam tests that are consistent with abnormal vestibular input, but normal vestibulo-ocular reflexes and apparently normal motor performance during swimming. Thus, degradation of RA during embryogenesis is required for formation of highly specialized regions of the vestibular sensory epithelia with specific functions in detecting head motions.

Rationale: In this paper, the efficacy and safety of using navigated drilling and arthroscopy (NDA) to assist surgery for ulnar-radial joint dislocation caused by epiphyseal premature closure (EPC) are described. Deformity correction surgery was mentioned in the literature, but there were numerous complications, for example, poor correction, infection, neurovascular injury, osteofascial compartment syndrome, failure of internal fixation, and nonunion after osteotomy. In order to minimize surgical complications, we utilized navigated drilling to finish accuracy bone bridge resection and applied arthroscopy to assess wrist lesions., Patient Concerns: An 11-year-old male patient showed swelling and pain of the left wrist., Diagnoses: The patient was diagnosed with a postoperative of Kirschner wire internal fixation for epiphyseal injury, left lower ulnar-radial joint dislocation, left wrist deformity, and EPC., Interventions: A NDA was used to assist the bone bridge resection in this patient., Outcomes: Pain was relieved clearly in the patient. Dorsiflexion increased from 60.8° to 85.3°, palmar flexion increased from 45.3° to 65.8°, supination increased from 41.3° to 69.5°, and pronation increased from 31.6° to 62.9°. The preoperative disabilities of the arm, shoulder, and hand (DASH) score was 86.1, which was increased to 16.4 postoperatively. Surgery designing lasted for 2 minutes, bone bridge resection lasted for 56 minutes, and fluoroscopic time was 2.4 minutes. Complications, for example, neurological injury, vascular injury, infection and deformity aggressive, were not found during the 5-month follow up., Lessons: The outcome of the present study suggests that the NDA maximizes the bone bridge resection accuracy in EPC treatment, which is made efficient by reducing surgical trauma and avoiding neurovascular injury. An experience was gained that in the process of bone bridge removal, the bit of navigated drill should be continuously washed with normal saline to cool down, so as to avoid damage of nerve caused by heat conduction.

The semicircular canals of the mammalian inner ear are derived from epithelial pouches in which epithelial cells in the central region of each pouch undergo resorption, leaving behind the region at the rim to form a tube-shaped canal. Lack of proliferation at the rim and/or over-clearing of epithelial cells in the center of the pouch can obliterate canal formation. Otic-specific knockout of bone morphogenetic protein 2 ( Bmp2 ) results in absence of all three semicircular canals; however, the common crus and ampullae housing the sensory tissue (crista) are intact. The lack of Bmp2 causes Ntn1 (which encodes netrin 1), which is required for canal resorption, to be ectopically expressed at the canal rim. Ectopic Ntn1 results in reduction of Dlx5 and Lmo4 , which are required for rim formation. These phenotypes can be partially rescued by removing one allele of Ntn1 in the Bmp2 mutants, indicating that Bmp2 normally negatively regulates Ntn1 for canal formation. Additionally, non-resorption of the canal pouch in Ntn1 -/- mutants is partially rescued by removing one allele of Bmp2 Thus, reciprocal inhibition between Bmp2 and netrin 1 is involved in canal formation of the vestibule., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Transarterial chemoembolization (TACE) is the first-line treatment in patients with unresectable hepatocellular carcinoma (HCC). In recent years, there has been increasing clinical evidence that drug-eluting beads provide a combined ischemic and cytotoxic effect that may be superior to conventional TACE, with low systemic toxicity. The therapeutic value of TACE performed using the embolic microsphere DC Bead loaded with doxorubicin (drug-eluting bead doxorubicin [DEBDOX]) has been shown by several randomized controlled trials. Since Lencioni et al. [Cardiovasc Intervent Radiol 2012; 35: 980-985] published the first widely accepted technical recommendations on HCC embolization with DEBDOX-TACE in 2012, new studies have contributed to a better understanding of when and how to apply this new therapeutic modality, and they have yet to be incorporated into an updated guideline. Additionally, differences in the underlying liver pathology and practice of transcatheter embolization between Asian and Western populations have not been adequately addressed, and there remain significant variations in the TACE protocols adopted in different parts of the world. These mainly revolve around the number and type of chemotherapeutic agents used, type of embolic material, reliance on Lipiodol, and selectivity of catheter positioning. As a result of these issues, it has been difficult to interpret and compare results obtained from different centers in a systematic fashion. To address these concerns, we convened a panel of experts specializing in different aspects of HCC treatment to craft an updated set of recommendations that better reflect recent clinical experiences and are tailored to the use of DEBDOX-TACE in Taiwan. The conclusions of this expert panel are described in the following article.

LIM-domain containing transcription factors (LIM-TFs) are conserved factors important for embryogenesis. The specificity of these factors in transcriptional regulation is conferred by the complexes that they form with other proteins such as LIM-domain-binding (Ldb) proteins and LIM-domain only (LMO) proteins. Unlike LIM-TFs, these proteins do not bind DNA directly. LMO proteins are negative regulators of LIM-TFs and function by competing with LIM-TFs for binding to Ldb's. Although the LIM-TF Lmx1a is expressed in the developing mouse hindbrain, which provides many of the extrinsic signals for inner ear formation, conditional knock-out embryos of both sexes show that the inner ear source of Lmx1a is the major contributor of ear patterning. In addition, we have found that the reciprocal interaction between Lmx1a and Lmo4 (a LMO protein within the inner ear) mediates the formation of both vestibular and auditory structures. Lmo4 negatively regulates Lmx1a to form the three sensory cristae, the anterior semicircular canal, and the shape of the utricle in the vestibule. Furthermore, this negative regulation blocks ectopic sensory formation in the cochlea. In contrast, Lmx1a negatively regulates Lmo4 in mediating epithelial resorption of the canal pouch, which gives rise to the anterior and posterior semicircular canals. We also found that Lmx1a is independently required for the formation of the endolymphatic duct and hair cells in the basal cochlear region. SIGNIFICANCE STATEMENT The mammalian inner ear is a structurally complex organ responsible for detecting sound and maintaining balance. Failure to form the intricate 3D structure of this organ properly during development most likely will result in sensory deficits on some level. Here, we provide genetic evidence that a transcription factor, Lmx1a, interacts with its negative regulator, Lmo4, to pattern various vestibular and auditory components of the mammalian inner ear. Identifying these key molecules that mediate formation of this important sensory organ will be helpful for designing strategies and therapeutics to alleviate hearing loss and balance disorders., (Copyright © 2018 Huang et al.)

Competing Interests: Competing interests: None declared.

The orientation of hair bundles on top of sensory hair cells (HCs) in neuromasts of the lateral line system allows fish to detect direction of water flow. Each neuromast shows hair bundles arranged in two opposing directions and each afferent neuron innervates only HCs of the same orientation. Previously, we showed that this opposition is established by expression of Emx2 in half of the HCs, where it mediates hair bundle reversal (Jiang et al., 2017). Here, we show that Emx2 also regulates neuronal selection: afferent neurons innervate either Emx2-positive or negative HCs. In emx2 knockout and gain-of-function neuromasts, all HCs are unidirectional and the innervation patterns and physiological responses of the afferent neurons are dependent on the presence or absence of Emx2. Our results indicate that Emx2 mediates the directional selectivity of neuromasts by two distinct processes: regulating hair bundle orientation in HCs and selecting afferent neuronal targets., Competing Interests: YJ, SW, TJ, DW, KK No competing interests declared

Colorectal cancer (CRC) is a common gastrointestinal cancer, with a high incidence and high mortality. Long non-coding RNAs (lncRNAs) are involved in the development, invasion and metastasis, early diagnosis, prognosis, the chemoresistance and radioresistance of CRC through interference with mRNA activity, directly combining with proteins to regulate their activity or alter their localization, influencing downstream gene expression by inhibiting RNA polymerase and regulating gene expression as competing endogenous RNAs. Recent progress in next generation sequencing and transcriptome analysis has revealed that tissue and cancer-type specific lncRNAs could be useful prognostic markers. Here, the CRC-associated lncRNAs from recent studies until October 2016 are reviewed and multiple studies that have confirmed CRC-associated lncRNAs are summarized. This review may be helpful in understanding the overall relationships between the lncRNAs involved in CRC.

The asymmetric location of stereociliary bundle (hair bundle) on the apical surface of mechanosensory hair cells (HCs) dictates the direction in which a given HC can respond to cues such as sound, head movements, and water pressure. Notably, vestibular sensory organs of the inner ear, the maculae, exhibit a line of polarity reversal (LPR) across which, hair bundles are polarized in a mirror-image pattern. Similarly, HCs in neuromasts of the zebrafish lateral line system are generated as pairs, and two sibling HCs develop opposite hair bundle orientations. Within these sensory organs, expression of the transcription factor Emx2 is restricted to only one side of the LPR in the maculae or one of the two sibling HCs in neuromasts. Emx2 mediates hair bundle polarity reversal in these restricted subsets of HCs and generates the mirror-image pattern of the sensory organs. Downstream effectors of Emx2 control bundle polarity cell-autonomously via heterotrimeric G proteins.

The adverse reactions of warfarin that were found mainly occurred in the first month. This study was carried out to observe the effect of gene polymorphisms on the warfarin therapy at the initial stage. Four-hundred and sixty Chinese patients began warfarin treatment with daily 2.5 mg after heart valve replacement operations were enrolled. The daily international normalized ratio (INR) for anticoagulation were recorded till the seventh day. Blood samples were collected and used to detect genotypes for VKORC1 rs7294, CYP2C9 rs1057910, CYP4F2 rs2108622 and ORM1 rs17650. INR and their changes were compared among genotypes. INR was partially correlated with the VKORC1 rs7294, CYP2C9 rs1057910, CYP4F2 rs2108622 and ORM1 rs17650 polymorphisms from the third, fourth and sixth day on, respectively. VKORC1 rs7294 and CYP4F2 rs2108622 carriers responded lower than the wild genotype, whereas CYP2C9 rs1057910 and ORM1 rs17650 carriers responded higher, respectively. Fifty percent of AA/*1*3/CC/*S*S patients and 16% of AA/*1*1/CC/*S*S patients were over anticoagulation treated with INR >4.0 at the third day. Ninety percent of VKORC1 rs7294 carrier patients have INR <1.63, a mark of the 25% of lower responders of the wild genotype. Our study provided another kind of evidence that VKORC1 rs7294, CYP2C9 rs1057910, CYP4F2 rs2108622 and ORM1 rs17650 affected the action of warfarin in different styles. Patients with AA/*1*1/CC/*S*S, AA/*1*3/CC/*S*S should use a less initial dosage to avoid over anticoagulation, and patients with VKORC1 rs7294 should use larger initial dose to proof an effective therapy.

The inner ear is a complex organ comprised of various specialized sensory organs for detecting sound and head movements. The timing of specification for these sensory organs, however, is not clear. Previous fate mapping results of the inner ear indicate that vestibular and auditory ganglia and two of the vestibular sensory organs, the utricular macula (UM) and saccular macula (SM), are lineage related. Based on the medial-lateral relationship where respective auditory and vestibular neuroblasts exit from the otic epithelium and the subsequent formation of the medial SM and lateral UM in these regions, we hypothesized that specification of the two lateral structures, the vestibular ganglion and the UM are coupled and likewise for the two medial structures, the auditory ganglion and the SM. We tested this hypothesis by surgically inverting the primary axes of the otic cup in ovo and investigating the fate of the vestibular neurogenic region, which had been spotted with a lipophilic dye. Our results showed that the laterally-positioned, dye-associated, vestibular ganglion and UM were largely normal in transplanted ears, whereas both auditory ganglion and SM showed abnormalities suggesting the lateral but not the medial-derived structures were mostly specified at the time of transplantation. Both of these results are consistent with a temporal coupling between neuronal and macular fate specifications., (Published by Elsevier Inc.)

We measured the effect of Schwann cell transplantation and complement factor 5a (C5a) receptor antagonist on nerve function recovery in rats with spinal cord injury. Experimental spinal cord injury was induced in eighty Wistar rats and these were randomly divided into four treatment groups: culture medium and saline injection (control group), Schwann cell injection (cell transplantation group), C5a receptor antagonist injection (C5a receptor antagonist group), and both Schwann cell and C5a receptor antagonist injections (combination group). Rear limb functional recovery was assessed 1, 2, 4, 6, and 8 weeks after the spinal cord injury with the tilt table test and the Basso, Beattie, Bresnahan scale. Sex-determining region Y (SRY) gene expression was measured at week 4 and horseradish peroxidase (HRP) labeling was used at week 8 to further assess the recovery of neuroelectrophysiological functions. The rear limb functional assessment showed that the combination group had better outcomes than the cell transplantation and C5a receptor antagonist groups. All treatment groups had better outcomes than control. Only the cell transplantation and combination groups showed SRY expression. The number of HRP-positive nerve fibers in the different groups ranked as follows: combination group > cell transplantation and C5a receptor antagonist > control. The refractory period and amplitude of the induced potential in the combination group were significantly greater than in the other three groups. These results suggest that the combination of Schwann cell transplantation and the C5a receptor antagonist enhances the regeneration of injured synapses and improves limb function and electrophysiology.

Schwann cell transplantation and hyperbaric oxygen therapy each promote recovery from spinal cord injury, but it remains unclear whether their combination improves therapeutic results more than monotherapy. To investigate this, we used Schwann cell transplantation via the tail vein, hyperbaric oxygen therapy, or their combination, in rat models of spinal cord contusion injury. The combined treatment was more effective in improving hindlimb motor function than either treatment alone; injured spinal tissue showed a greater number of neurite-like structures in the injured spinal tissue, somatosensory and motor evoked potential latencies were notably shorter, and their amplitudes greater, after combination therapy than after monotherapy. These findings indicate that Schwann cell transplantation combined with hyperbaric oxygen therapy is more effective than either treatment alone in promoting the recovery of spinal cord in rats after injury.

Here we demonstrate association of variants in the mitochondrial asparaginyl-tRNA synthetase NARS2 with human hearing loss and Leigh syndrome. A homozygous missense mutation ([c.637G>T; p.Val213Phe]) is the underlying cause of nonsyndromic hearing loss (DFNB94) and compound heterozygous mutations ([c.969T>A; p.Tyr323*] + [c.1142A>G; p.Asn381Ser]) result in mitochondrial respiratory chain deficiency and Leigh syndrome, which is a neurodegenerative disease characterized by symmetric, bilateral lesions in the basal ganglia, thalamus, and brain stem. The severity of the genetic lesions and their effects on NARS2 protein structure cosegregate with the phenotype. A hypothetical truncated NARS2 protein, secondary to the Leigh syndrome mutation p.Tyr323* is not detectable and p.Asn381Ser further decreases NARS2 protein levels in patient fibroblasts. p.Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNAAsn in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome.

Sound frequency discrimination begins at the organ of Corti in mammals and the basilar papilla in birds. Both of these hearing organs are tonotopically organized such that sensory hair cells at the basal (proximal) end respond to high frequency sound, whereas their counterparts at the apex (distal) respond to low frequencies. Sonic hedgehog (Shh) secreted by the developing notochord and floor plate is required for cochlear formation in both species. In mice, the apical region of the developing cochlea, closer to the ventral midline source of Shh, requires higher levels of Shh signaling than the basal cochlea farther away from the midline. Here, gain-of-function experiments using Shh-soaked beads in ovo or a mouse model expressing constitutively activated Smoothened (transducer of Shh signaling) show up-regulation of apical genes in the basal cochlea, even though these regionally expressed genes are not necessarily conserved between the two species. In chicken, these altered gene expression patterns precede morphological and physiological changes in sensory hair cells that are typically associated with tonotopy such as the total number of stereocilia per hair cell and gene expression of an inward rectifier potassium channel, IRK1, which is a bona fide feature of apical hair cells in the basilar papilla. Furthermore, our results suggest that this conserved role of Shh in establishing cochlear tonotopy is initiated early in development by Shh emanating from the notochord and floor plate.

The temporal bone encases conductive and sensorineural elements of the ear. Mutations of POU3F4 are associated with unique temporal bone abnormalities and X-linked mixed deafness (DFNX2/DFN3). However, the target genes and developmental processes controlled by POU3F4 transcription factor activity have remained largely uncharacterized. Ephrin-B2 (Efnb2) is a signaling molecule with well-documented effects on cell adhesion, proliferation, and migration. Our analyses of targeted mouse mutants revealed that Efnb2 loss-of-function phenocopies temporal bone abnormalities of Pou3f4 hemizygous null neonates: qualitatively identical malformations of the stapes, styloid process, internal auditory canal, and cochlear capsule were present in both mutants. Using failed/insufficient separation of the stapes and styloid process as a quantitative trait, we found that single gene Efnb2 loss-of-function and compound Pou3f4/Efnb2 loss-of-function caused a more severe phenotype than single gene Pou3f4 loss-of-function. Pou3f4 and Efnb2 gene expression domains overlapped at the site of impending stapes-styloid process separation and at subcapsular mesenchyme surrounding the cochlea; at both these sites, Efnb2 expression was attenuated in Pou3f4 hemizygous null mutants relative to control. Results of immunoprecipitation experiments using chromatin isolated from nascent middle ear mesenchyme supported the hypothesis of a physical association between Pou3f4 and specific non-coding sequence of Efnb2. We propose that Efnb2 is a target of Pou3f4 transcription factor activity and an effector of mesenchymal patterning during temporal bone development.

Control over ionic composition and volume of the inner ear luminal fluid endolymph is essential for normal hearing and balance. Mice deficient in either the EphB2 receptor tyrosine kinase or the cognate transmembrane ligand ephrin-B2 (Efnb2) exhibit background strain-specific vestibular-behavioral dysfunction and signs of abnormal endolymph homeostasis. Using various loss-of-function mouse models, we found that Efnb2 is required for growth and morphogenesis of the embryonic endolymphatic epithelium, a precursor of the endolymphatic sac (ES) and duct (ED), which mediate endolymph homeostasis. Conditional inactivation of Efnb2 in early-stage embryonic ear tissues disrupted cell proliferation, cell survival, and epithelial folding at the origin of the endolymphatic epithelium. This correlated with apparent absence of an ED, mis-localization of ES ion transport cells relative to inner ear sensory organs, dysplasia of the endolymph fluid space, and abnormally formed otoconia (extracellular calcite-protein composites) at later stages of embryonic development. A comparison of Efnb2 and Notch signaling-deficient mutant phenotypes indicated that these two signaling systems have distinct and non-overlapping roles in ES/ED development. Homozygous deletion of the Efnb2 C-terminus caused abnormalities similar to those found in the conditional Efnb2 null homozygote. Analyses of fetal Efnb2 C-terminus deletion heterozygotes found mis-localized ES ion transport cells only in the genetic background exhibiting vestibular dysfunction. We propose that developmental dysplasias described here are a gene dose-sensitive cause of the vestibular dysfunction observed in EphB-Efnb2 signaling-deficient mice., (Published by Elsevier Inc.)

Neural precursor cells of the central nervous system undergo successive temporal waves of terminal division, each of which is soon followed by the onset of cell differentiation. The organ of Corti in the mammalian cochlea develops differently, such that precursors at the apex are the first to exit from the cell cycle but the last to begin differentiating as mechanosensory hair cells. Using a tissue-specific knockout approach in mice, we show that this unique temporal pattern of sensory cell development requires that the adjacent auditory (spiral) ganglion serve as a source of the signaling molecule Sonic hedgehog (Shh). In the absence of this signaling, the cochlear duct is shortened, sensory hair cell precursors exit from the cell cycle prematurely, and hair cell differentiation closely follows cell cycle exit in a similar apical-to-basal direction. The dynamic relationship between the restriction of Shh expression in the developing spiral ganglion and its proximity to regions of the growing cochlear duct dictates the timing of terminal mitosis of hair cell precursors and their subsequent differentiation., Competing Interests: The authors declare no conflict of interest.

Sox2 is required for proper neuronal formation in the CNS, but the molecular mechanisms involved are not well characterized. Here, we addressed the role of Sox2 in neurogenesis of the developing chicken inner ear. Overexpressing Sox2 from a constitutive (β-actin) promoter induces the expression of the proneural gene, Neurogenin1 (Ngn1); however, the expression of a downstream target of Ngn1, Neurod1, is unchanged. As a result, there is a reduction of neural precursors to delaminate and populate the developing cochleo-vestibular ganglion. In contrast, overexpression of either Ngn1 or Neurod1 is sufficient to promote the neural fate in this system. These results suggest that high levels of Sox2 inhibit progression of neurogenesis in the developing inner ear. Furthermore, we provide evidence that Ngn1 and Neurod1 inhibit Sox2 transcription through a phylogenetically conserved Sox2 enhancer to mediate neurogenesis. We propose that Sox2 confers neural competency by promoting Ngn1 expression, and that negative feedback inhibition of Sox2 by Ngn1 is an essential step in the progression from neural precursor to nascent neuron.

The inner ear is a structurally complex vertebrate organ built to encode sound, motion, and orientation in space. Given its complexity, it is not surprising that inner ear dysfunction is a relatively common consequence of human genetic mutation. Studies in model organisms suggest that many genes currently known to be associated with human hearing impairment are active during embryogenesis. Hence, the study of inner ear development provides a rich context for understanding the functions of genes implicated in hearing loss. This chapter focuses on molecular mechanisms of inner ear development derived from studies of model organisms.

Development of the mammalian inner ear requires coordination of cell proliferation, cell fate determination and morphogenetic movements. While significant progress has been made in identifying developmental signals required for inner ear formation, less is known about how distinct signals are coordinated by their downstream mediators. Members of the Rac family of small GTPases are known regulators of cytoskeletal remodeling and numerous other cellular processes. However, the function of Rac GTPases in otic development is largely unexplored. Here, we show that Rac1 and Rac3 redundantly regulate many aspects of inner ear morphogenesis. While no morphological defects were observed in Rac3(-/-) mice, Rac1(CKO); Rac3(-/-) double mutants displayed enhanced vestibular and cochlear malformations compared to Rac1(CKO) single mutants. Moreover, in Rac1(CKO); Rac3(-/-) mutants, we observed compromised E-cadherin-mediated cell adhesion, reduced cell proliferation and increased cell death in the early developing otocyst, leading to a decreased size and malformation of the membranous labyrinth. Finally, cochlear extension was severely disrupted in Rac1(CKO); Rac3(-/-) mutants, accompanied by a loss of epithelial cohesion and formation of ectopic sensory patches underneath the cochlear duct. The compartmentalized expression of otic patterning genes within the Rac1(CKO); Rac3(-/-) mutant otocyst was largely normal, however, indicating that Rac proteins regulate inner ear morphogenesis without affecting cell fate specification. Taken together, our results reveal an essential role for Rac GTPases in coordinating cell adhesion, cell proliferation, cell death and cell movements during otic development., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Gbx2 encodes a DNA-binding transcription factor that plays pivotal roles during embryogenesis. Gain-and loss-of-function studies in several vertebrate species have demonstrated a requirement for Gbx2 in development of the anterior hindbrain, spinal cord, inner ear, heart, and neural crest cells. However, the target genes through which GBX2 exerts its effects remain obscure. Using chromatin immunoprecipitation coupled with direct sequencing (ChIP-Seq) analysis in a human prostate cancer cell line, we identified cis-regulatory elements bound by GBX2 to provide insight into its direct downstream targets. The analysis revealed more than 286 highly significant candidate target genes, falling into various functional groups, of which 51% are expressed in the nervous system. Several of the top candidate genes include EEF1A1, ROBO1, PLXNA4, SLIT3, NRP1, and NOTCH2, as well as genes associated with the Usher syndrome, PCDH15 and USH2A, and are plausible candidates contributing to the developmental defects in Gbx2(-/-) mice. We show through gel shift analyses that sequences within the promoter or introns of EEF1A1, ROBO1, PCDH15, USH2A and NOTCH2, are directly bound by GBX2. Consistent with these in vitro results, analyses of Gbx2(-/-) embryos indicate that Gbx2 function is required for migration of Robo1-expressing neural crest cells out of the hindbrain. Furthermore, we show that GBX2 activates transcriptional activity through the promoter of EEF1A1, suggesting that GBX2 could also regulate gene expression indirectly via EEF1A. Taken together, our studies show that GBX2 plays a dynamic role in development and diseases.

Inner ear hair cells convert the mechanical stimuli of sound, gravity, and head movement into electrical signals. This mechanotransduction process is initiated by opening of cation channels near the tips of hair cell stereocilia. Since the identity of these ion channels is unknown, and mutations in the gene encoding transmembrane channel-like 1 (TMC1) cause hearing loss without vestibular dysfunction in both mice and humans, we investigated the contribution of Tmc1 and the closely related Tmc2 to mechanotransduction in mice. We found that Tmc1 and Tmc2 were expressed in mouse vestibular and cochlear hair cells and that GFP-tagged TMC proteins localized near stereocilia tips. Tmc2 expression was transient in early postnatal mouse cochlear hair cells but persisted in vestibular hair cells. While mice with a targeted deletion of Tmc1 (Tmc1(Δ) mice) were deaf and those with a deletion of Tmc2 (Tmc2(Δ) mice) were phenotypically normal, Tmc1(Δ)Tmc2(Δ) mice had profound vestibular dysfunction, deafness, and structurally normal hair cells that lacked all mechanotransduction activity. Expression of either exogenous TMC1 or TMC2 rescued mechanotransduction in Tmc1(Δ)Tmc2(Δ) mutant hair cells. Our results indicate that TMC1 and TMC2 are necessary for hair cell mechanotransduction and may be integral components of the mechanotransduction complex. Our data also suggest that persistent TMC2 expression in vestibular hair cells may preserve vestibular function in humans with hearing loss caused by TMC1 mutations.

The purpose of this study was to report our experience of percutaneous retrieval of dislodged port catheters with concurrent use of pigtail and loop snare catheters. During a 5-year period at our institute (June 2005 to July 2010), a total of 23 dislodged port catheters were retrieved. The interval between port catheter implantation and dislodged catheter retrieval ranged from 43 days to 1,414 days (mean 586.7 days). The time of delayed retrieval ranged from 1 day to 45 days (mean 4.6 days). All dislodged catheters were retrieved with the concurrent use of pigtail and loop snare catheters via femoral venous route. The prevalence of port catheter dislodgement at our institute was 3.4%. All dislodged port catheters were removed successfully with pigtail and loop snare catheters together. No procedure-related complications were encountered, except for transient arrhythmia in two patients, which required no medication. In conclusion, the concurrent use of pigtail and loop snare catheters is a feasible and easy way for percutaneous retrieval of a dislodged central venous port catheter., (Copyright © 2011. Published by Elsevier B.V.)

Vertebrate hearing and balance are based in complex asymmetries of inner ear structure. Here, we identify retinoic acid (RA) as an extrinsic signal that acts directly on the ear rudiment to affect its compartmentalization along the anterior-posterior axis. A rostrocaudal wave of RA activity, generated by tissues surrounding the nascent ear, induces distinct responses from anterior and posterior halves of the inner ear rudiment. Prolonged response to RA by posterior otic tissue correlates with Tbx1 transcription and formation of mostly nonsensory inner ear structures. By contrast, anterior otic tissue displays only a brief response to RA and forms neuronal elements and most sensory structures of the inner ear.

Kaposiform hemangioendothelioma is a very infrequent, locally aggressive vascular neoplasm, characterized by fascicular spindle cell proliferation. It occurs almost exclusively in infants and adolescents, and is often associated with Kasabach-Merritt phenomenon. The tumor is predominantly located subcutaneously or in the deep soft tissue of the extremities and trunk, peritoneum, or retroperitoneum. However, this tumor can sometimes be located on the head and neck. We report a case of kaposiform hemangioendothelioma of the maxillary sinus in a 4-month-old female infant presenting with cheek swelling, thrombocytopenia, anemia, and disseminated intravascular coagulation. Sinus computed tomography presented an enhancing, bone-destructing tumor. Magnetic resonance images showed an uncommon appearance as mostly low signal intensity on T2-weighted images., (Copyright 2010 Elsevier. Published by Elsevier B.V. All rights reserved.)

Gegen Qinlian dispensing granule, a favorite composite formula, is a combination of Radix Puerariae Lobatae, Radix Scutellariae, Rhizoma Coptidis and Radix et Rhizoma Glycyrrhizae Praeparata cum Melle. To develop a method to overall evaluate correlation between the formula and its four raw herbs, LC fingerprints of the formula and its raw herbs were developed and LC-DAD-MS was employed to identify the components in the formula fingerprint. According to the characteristic fragmentation behavior of known flavonoids, alkaloids and saponins isolated from the four raw herbs as well as retention time, UV and MS data of detected compounds, a total of 23 constituents in the formula fingerprint were structurally characterized. Chemical correlation between the formula and the four crude herbs was evaluated qualitatively and quantitatively by the developed LC fingerprints. The results showed that 8 components in the formula fingerprint were addressed to Radix Puerariae Lobatae, 11 to Radix Scutellariae, 7 to Rhizoma Coptidis, 3 to Radix et Rhizoma Glycyrrhizae Praeparata cum Melle, and that the relative area ratios of the common peaks in the formula vary slightly in comparison with corresponding ratios in its crude herbs, demonstrating the chemical constituents in the formula have patterns similar to those in its crude herbs., (Copyright 2009 Elsevier GmbH. All rights reserved.)

A mature inner ear is a complex structure consisting of vestibular and auditory components. Microsurgical ablations, rotations, and translocations were performed in ovo to identify the tissues that control inner ear morphogenesis. We show that mesenchyme/ectoderm adjacent to the developing ear specifically governs the shape of vestibular components - the semicircular canals and ampullae - by conferring anteroposterior axial information to these structures. In contrast, removal of individual hindbrain rhombomeres adjacent to the developing ear preferentially affects the growth and morphogenesis of the auditory subdivision, the cochlear duct, or basilar papilla. Removal of rhombomere 5 affects cochlear duct growth, while rhombomere 6 removal affects cochlear growth and morphogenesis. Rotating rhombomeres 5 and 6 along the anteroposterior axis also impacts cochlear duct morphogenesis but has little effect on the vestibular components. Our studies indicate that discrete tissues, acting at a distance, control the morphogenesis of distinct elements of the inner ear. These results provide a basis for identifying factors that are essential to vestibular and auditory development in vertebrates., (Copyright 2009. Published by Elsevier Inc.)

Accurate and consistent visualization of the entire coronary system with high-grade imaging quality is crucial for routine applications of multi-detector-computed tomography (MDCT) coronary angiography. To determine the imaging quality of 64-slice-MDCT coronary angiography, we respectively explored the quantitative parameters of imaging quality in 105 consecutive subjects (71 men, 34 women; aged 58.66 +/- 10.62 years) who underwent 64-slice-MDCT coronary angiography to screen for coronary disease. The interobserver agreement for semi-quantitative image quality, visible length, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the coronary arteries was good. The SNR and CNR of the proximal segments of the coronary arteries were superior to that of the distal segments of coronary arteries (p < 0.001). The visible length of the stenosed right coronary artery was significantly shorter than that of the non-stenosed right coronary artery (p = 0.03). The SNR and CNR of the stenosed and non-stenosed coronary arteries revealed no significant difference (p > 0.05). Body weight and body mass index were inversely related to the SNR and CNR of the aorta (p < 0.001). In conclusion, 64-slice-MDCT coronary angiography can provide excellent imaging quality of coronary arteries in subjects undergoing screening for coronary disease, although the SNR and CNR were relatively low at the distal segments of coronary arteries.

San-ao decoction (SAD), comprising Herba Ephedrae, Radix et Rhizoma Glycyrrhizae and Seneb Armeniacae Amarum, is one of the most popular traditional Chinese medicine (TCM) formulae for asthma. Peroxisome proliferator-activated receptors (PPARs) areey regulators of lipid and glucose metabolism and have become important therapeutic targets for various deseases, PPARgamma activation might exhibit anti-inflammatory properties in different chronic inflammatory processes. The EtOAc fraction of SAD showed a significant effect on PPARgamma activation. A simple and rapid method has been established for separation and characterization of the main compounds in the PPARgamma-activating fraction of SAD by ultra-fast HPLC coupled with quadropole time-of-flight mass pectrometry (UPLC-Q-TOF/MS). A total of 10 compounds were identified in the activating fraction of SAD, including amygdalin (1), liquiritin (2), 6'-acetyliquiritin (3), liquiritigenin (4), isoliquiritigenin (5), formononetin (6), licoisoflavanone (7), glycycoumarin (8), glycyrol (9) and uercetin (10). The results also characterized formononetin as a predominant component in this fraction. The dose-effect relationship comparison study of formononetin and the EtOAc fraction of SAD by adding formononetin was performed, the results suggested that formononetin was the major component of the EtOAc fraction of SAD responsible for activating PPARgamma, and the method will possibly be applied to study the complex biological active constituents of other TCMs.

Lmx1a is a LIM homeodomain-containing transcription factor, which is required for the formation of multiple organs. Lmx1a is broadly expressed in early stages of the developing inner ear, but its expression is soon restricted to the non-sensory regions of the developing ear. In an Lmx1a functional null mutant, dreher (dr(J)/dr(J)), the inner ears lack a non-sensory structure, the endolymphatic duct, and the membranous labyrinth is poorly developed. These phenotypes are consistent with Lmx1a's role as a selector gene. More importantly, while all three primary fates of the inner ear - neural, sensory, and non-sensory - are specified in dr(J)/dr(J), normal boundaries among these tissues are often violated. For example, the neurogenic domain of the ear epithelium, from which cells delaminate to form the cochleovestibular ganglion, is expanded. Within the neurogenic domain, the demarcation between the vestibular and auditory neurogenic domains is most likely disrupted as well, based on the increased numbers of vestibular neuroblasts and ectopic expression of Fgf3, which normally is associated specifically with the vestibular neurogenic region. Furthermore, aberrant and ectopic sensory organs are observed; most striking among these is vestibular-like hair cells located in the cochlear duct.

We demonstrate the spectral and spatial reconfigurability of photonic crystal double-heterostructure cavities in silicon by microfluidic infiltration of selected air holes. The lengths of the microfluidic cavities are changed by adjusting the region of infiltrated holes in steps of several microns. We systematically investigate the spectral signature of these cavities, showing high Q-factor resonances for a broad range of cavity lengths. The fluid can be removed by immersing the device in toluene, offering complete reconfigurability. Our cavity writing technique allows for tolerances in the infiltration process and provides flexibility as it can be employed at any time after photonic crystal fabrication.

Background: The main pulmonary arterial (PA) distensibility in patients with pulmonary hypertension (PH) and pulmonary embolism (PE) is uncertain., Methods and Results: We enrolled 45 patients with echocardiographic signs of PH and without imaging evidence of PE, and another 45 who were found by multidetector-row computed tomography to have PE. Fifty normal patients served as a control group. The PA distensibility was calculated from the change in main PA diameter between diastole and systole, as the maximal systolic diameter minus the minimal diastolic diameter divided by the minimal diastolic diameter. The PA distensibility is lowest in PH (6.0+/-2.7%), followed by PE (12.9+/-3.4%) and then the normal controls (25.9+/-5.7%). Statistical analysis of data obtained from patients with PE or PH reveals that a PA distensibility of >8.3% could be used to identify PE with a sensitivity of 83% and a specificity of 82%. After a 3-month anticoagulation, 22 of 45 PE patients had complete resolution of thrombus; 23 had residual thrombus. The PE patients, regardless of residual thrombus presence, had significant improvement of PA distensibility after a 3-month anticoagulation, although the diameters of main PA did not shrink., Conclusion: PA distensibility is a method to distinguish acute PE from chronic PH.

Angular head movements in vertebrates are detected by the three semicircular canals of the inner ear and their associated sensory tissues, the cristae. Bone morphogenetic protein 4 (Bmp4), a member of the Transforming growth factor family (TGF-beta), is conservatively expressed in the developing cristae in several species, including zebrafish, frog, chicken, and mouse. Using mouse models in which Bmp4 is conditionally deleted within the inner ear, as well as chicken models in which Bmp signaling is knocked down specifically in the cristae, we show that Bmp4 is essential for the formation of all three cristae and their associated canals. Our results indicate that Bmp4 does not mediate the formation of sensory hair and supporting cells within the cristae by directly regulating genes required for prosensory development in the inner ear such as Serrate1 (Jagged1 in mouse), Fgf10, and Sox2. Instead, Bmp4 most likely mediates crista formation by regulating Lmo4 and Msx1 in the sensory region and Gata3, p75Ngfr, and Lmo4 in the non-sensory region of the crista, the septum cruciatum. In the canals, Bmp2 and Dlx5 are regulated by Bmp4, either directly or indirectly. Mechanisms involved in the formation of sensory organs of the vertebrate inner ear are thought to be analogous to those regulating sensory bristle formation in Drosophila. Our results suggest that, in comparison to sensory bristles, crista formation within the inner ear requires an additional step of sensory and non-sensory fate specification., Competing Interests: The authors have declared that no competing interests exist.