Autoimmune regulator (Aire) mutations result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), which manifests as multi-organ autoimmunity and chronic mucocutaneous candidiasis (CMC). Indendritic cells (DCs), pattern recognition receptors (PRR), such as Toll-like receptors (TLRs), are closely involved in the recognition of various pathogens, activating the intercellular signaling pathway, followed by the activation of transcription factors and the expression of downstream genes, which take part in mediating the immune response and maintaining immune tolerance. In this study, we found that Aire up-regulated TLR3 expression and modulated the downstream cytokine expression and nuclear factor-κB (NF-κB) of the TLR3 signaling pathway.
autoimmune regulator; immune tolerance; TLR3
The airway epithelium of chronic obstructive pulmonary disease (COPD) patients undergoes aberrant repair and remodeling after repetitive injury following exposure to environmental factors. Abnormal airway regeneration observed in COPD is thought to originate in the stem/progenitor cells of the airway epithelium, the basal cells (BCs). However, the molecular mechanisms underlying these changes remain unknown. Here, trophoblast cell surface antigen 2 (TROP2), a protein implicated in the regulation of stem cell activity, was examined in lung tissue samples from COPD patients.
The expression of TROP2 and hyperplasia index Ki67 was assessed in lung epithelium specimens from non-smokers (n = 24), smokers (n = 24) and smokers with COPD (n = 24). Primary airway BCs were isolated by bronchoscopy from healthy individuals and COPD patients and subsequently transfected with pcDNA3.1-TROP2 or siRNA sequence in vitro. The functional consequences of TROP2 overexpression in BCs were explored.
Immunohistochemistry and immunofluorescence revealed increased TROP2 expression in airway BCs in smokers with COPD compared to nonsmokers and smokers without COPD, and staining was highly localized to hyperplastic regions containing Ki67 positive cells. TROP2 expression was also inversely correlated with airflow limitation in patients with COPD (r = −0.53, P < 0.01). pcDNA3.1-TROP2-BCs in vitro exhibited improved proliferation with activation of ERK1/2 phosphorylation signaling pathway. In parallel, changes in vimentin and E-cadherin in pcDNA3.1-TROP2-BCs were consistent with an epithelial-mesenchymal transition (EMT)-like change, and secretion of inflammatory factors IL-1β, IL-8 and IL-6 was increased. Moreover, down-regulation of TROP2 by siRNA significantly attenuated the proliferation of BCs derived from COPD patients. EMT-like features and cytokine levels of COPD basal cells were also weakened following the down-regulation of TROP2.
The results indicate that TROP2 may play a crucial role in COPD by affecting BC function and thus airway remodeling through increased BC hyperplasia, EMT-like change, and introduction of inflammatory molecules into the microenvironment.
Airway remodeling; Basal cells; Chronic obstructive pulmonary disease (COPD); Cigarette smoke; Trophoblast cell surface antigen 2 (TROP2)
Confocal endomicroscopy is an emerging imaging technology that has recently been introduced into the clinic to instantaneously collect “optical biopsies” in vivo with histology-like quality. Here, we demonstrate a fast scanner located in the distal end of a side-viewing instrument using a compact lens assembly with numerical aperture of 0.5 to achieve a working distance of 100 μm and field-of-view of 300 × 400 μm2. The microelectromechanical systems (MEMS) mirror was designed based on the principle of parametric resonance and images at 5 frames per second. The instrument has a 4.2 mm outer diameter and 3 cm rigid length, and can pass through the biopsy channel of a medical endoscope. We achieved real time optical sections of NIR fluorescence with 0.87 μm lateral resolution, and were able to visualize in vivo binding of a Cy5.5-labeled peptide specific for EGFR to the cell surface of pre-cancerous colonocytes within the epithelium of dysplastic crypts in mouse colon. By performing targeted imaging with endomicroscopy, we can visualize molecular expression patterns in vivo that provide a biological basis for disease detection.
Hepatitis C virus (HCV) establishes persistent infection in most infected patients, and eventually causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma in some patients. Monocytes and macrophages provide the first line of defense against pathogens, but their roles in HCV infection remains unclear. We have reported that HCV core protein (HCVc) manipulates human blood-derived dendritic cell development. In the present study, we tested whether HCVc affects human blood-derived monocyte differentiating into macrophages. Results showed that HCVc inhibits monocyte differentiation to either M1 or M2 macrophages through TLR2, associated with impaired STATs signaling pathway. Moreover, HCVc inhibits phagocytosis activity of M1 and M2 macrophages, M1 macrophage-induced autologous and allogeneic CD4+ T cell activation, but promotes M2 macrophage-induced autologous and allogeneic CD4+ T cell activation. In conclusion, HCVc inhibits monocyte-derived macrophage polarization via TLR2 signaling, leading to dysfunctions of both M1 and M2 macrophages in chronic HCV infected patients. This may contribute to the mechanism of HCV persistent infection, and suggest that blockade of HCVc might be a novel therapeutic approach to treating HCV infection.
Obstructive sleep apnea (OSA) has been associated with changes in brain structure and regional function in certain brain areas. However, the functional features of network organization in the whole brain remain largely uncertain. The purpose of this study was to identify the OSA-related spatial centrality distribution of the whole brain functional network and to investigate the potential altered intrinsic functional hubs.
Forty male patients with newly confirmed severe OSA on polysomnography, and well-matched good sleepers, participated in this study. All participants underwent a resting-state functional MRI scan and clinical and cognitive evaluation. Voxel-wise degree centrality (DC) was measured across the whole brain, and group difference in DC was compared. The relationship between the abnormal DC value and clinical variables was assessed using a linear correlation analysis.
Remarkably similar spatial distributions of the functional hubs (high DC) were found in both groups. However, OSA patients exhibited a pattern of significantly reduced regional DC in the left middle occipital gyrus, posterior cingulate cortex, left superior frontal gyrus, and bilateral inferior parietal lobule, and DC was increased in the right orbital frontal cortex, bilateral cerebellum posterior lobes, and bilateral lentiform nucleus, including the putamen, extending to the hippocampus, and the inferior temporal gyrus, which overlapped with the functional hubs. Furthermore, a linear correlation analysis revealed that the DC value in the posterior cingulate cortex and left superior frontal gyrus were positively correlated with Montreal cognitive assessment scores, The DC value in the left middle occipital gyrus and bilateral inferior parietal lobule were negatively correlated with apnea-hypopnea index and arousal index in OSA patients.
Our findings suggest that OSA patients exhibited specific abnormal intrinsic functional hubs including relatively reduced and increased DC. This expands our understanding of the functional characteristics of OSA, which may provide new insights into understanding the dysfunction and pathophysiology of OSA patients.
Hypertensive intracerebral hemorrhage (HICH) is one of the most devastating forms of stroke. Currently, no specific therapies for HICH except general medical care. However, in China, medicine of promoting blood circulation (PBC) and removing blood stasis (RBS) are widely and efficiently used to treat HICH and become a potentially effective treatment for the secondary effects of HICH to alleviate brain injury, accelerate neuronal recovery, and improve the prognosis. In order to evaluate the safety and effect of PBC and RBS herbal drugs, we design a prospective, randomized, open, double-blind controlled clinical trial on the hematoma enlargement in HICH patients treating with PBC and RBS herbal medicine within 6 h time window from the symptom onset.
A multicenter, three-group, prospective, randomized, double-blinded and placebo-controlled clinical trial. Patients aged 18 or older with HICH confirmed by CT scan within 6 h from the onset are included. 360 patients will be randomized to 3 groups (PBC & RBS & Placebo) within 6 h of ictus. Stratified block randomization is undertaken using a sequentially numbered and opaque envelope. All subjects must take medicine within 6 h of ictus and have another CT scan at about 24 h to confirm hematoma expansion. A postal questionnaire to the patients to evaluate their recorvery at 3 months. Primary outcome is the percent change in the volume of hematoma at 24 h. Secondary outcomes include: mortality, disability, serious adverse events, etc.
The CRRICH Trial is expected to confirm the safety and effect of acute intracerebral hemorrhage treated within 6 h of ictus with “RBS” therapy and to determine whether the traditional therapy can cause hematoma growth after intracerebral hemorrhage.
This is the first prospective, multicenter, randomized, placebo-controlled clinical trial to investigate herbal medicine whether can induce the incidence of hematoma enlargement of AICH patient within the 6 h time window from onset. We need the data to keep the herbal clinical usage safety.
Trial registration clinicaltrials.gov: NCT01918722
Intracerebral hemorrhage; Clinical trial; Traditional Chinese medicine; Promoting blood circulation; Removing blood stasis
Aim. To investigate the effect of Tongxinluo (Txl), a Chinese herbal compound, on diabetic peripheral neuropathy (DPN). Methods and Results. Diabetic rat model was established by peritoneal injection of streptozotocin (STZ). Txl ultrafine powder treatment for 16 weeks from the baseline significantly reversed the impairment of motor nerve conductive velocity (MNCV), mechanical hyperalgesia, and nerve structure. We further proved that Tongxinluo upregulates PGC-1α and its downstream factors including COX IV and SOD, which were involved in mitochondrial biogenesis. Conclusion. Our study indicates that the protective effect of Txl in diabetic neuropathy may be attributed to the induction of PGC-1α and its downstream targets. This finding may further illustrate the pleiotropic effect of the medicine.
Purpose: To develop a novel technique of percutaneous kyphoplasty (PKP) with effective biomechanical strength and lower radiation exposure. Methods: Thirty fresh lumbar vertebrae isolated from six hogs were decalcified and compressed to induce osteoporotic vertebral compression fractures. Kyphoplasty was performed using three different techniques (ten for each group): conventional unilateral approach (group A), conventional bilateral approach (group B) and novel unilateral approach (group C). Biomechanical indexes including Yield load and stiffness were tested before and after kyphoplasty. The anterior height of each vertebral body (AHVB) was measured before compression, after compression and after kyphoplasty. Frequency of C-arm use and volume of bone cement were also recorded in the process. Results: Compared with group A, our novel technique in group C can significantly improve the recovery of AHVB after compression fractures. However, there was no statistical difference between group B and group C. Values of Yield load in both group B and group C were statistically higher than that in group A, however, no significant difference was found between group B and C. Statistical results of stiffness were similar to Yield load. Regarding volume of bone cement and radiation exposure, the novel technique in group C needed more bone cement and fluoroscopy use than in group A but less than in group B. Conclusions: This novel device makes unilateral kyphoplasty feasible, safe and effective. In the premise of guaranteed biomechanical strength, the new technique significantly reduces risk of radiation exposure in kyphoplasty.
Compression fracture; unilateral percutaneous kyphoplasty; biomechanics; radiation exposure; bone cement leakage
Purpose: The Wiltse approach allows spinal surgeries to be performed with minimal soft tissue trauma. The purpose of this study was to investigate the anatomy of the natural cleavage plane between multifidus and longissimus at different levels based on MRI images. Methods: MRI cross-sectional scans from L1 to S1 were collected from 205 out patients (103 males, 102 females). Based on the images, some parameters were defined and measured to describe the locations, curvature and directions of Wiltse approach. Besides, differences of these parameters between genders and segments were compared. Results: Among the total of 2460 one-sided images, cleavage planes between multifidus and longissimus were not able to be identified in 105 images. The locations, directions and curvature of the cleavage plane differed significantly among different segments but followed some regular pattern from L1-S1. The simultaneous rotation of the plane around its deepest points to the midline from S1 to L1 and the plane seemed to be the most curved at L3 and relatively straight for L5 and S1. Conclusions: With a better understanding of the natural cleavage plane between multifidus and longissimus, performers can correctly plan the distance of skin incisions from the midline and the direction of muscle dissection at each vertebral level, thus reducing trauma in the operation.
Wiltse; minimal invasive; anatomy; lumbar spine; MRI
Autoimmune regulator (Aire) can promote the ectopic expression of peripheral tissue-restricted antigens (TRAs) in thymic medullary epithelial cells (mTECs), which leads to the deletion of autoreactive T cells and consequently prevents autoimmune diseases. However, the functions of Aire in the periphery, such as in dendritic cells (DCs), remain unclear. This study’s aim was to investigate the effect of Aire-overexpressing DCs (Aire cells) on the functions of CD4+ T cells and the treatment of type 1 diabetes (T1D). We demonstrated that Aire cells upregulated the mRNA levels of the tolerance-related molecules CD73, Lag3, and FR4 and the apoptosis of CD4+ T cells in STZ-T1D mouse-derived splenocytes. Furthermore, following insulin stimulation, Aire cells decreased the number of CD4+ IFN-γ+ T cells in both STZ-T1D and WT mouse-derived splenocytes and reduced the expression levels of TCR signaling molecules (Ca2+ and p-ERK) in CD4+ T cells. We observed that Aire cells-induced CD4+ T cells could delay the development of T1D. In summary, Aire-expressing DCs inhibited TCR signaling pathways and decreased the quantity of CD4+IFN-γ+ autoreactive T cells. These data suggest a mechanism for Aire in the maintenance of peripheral immune tolerance and provide a potential method to control autoimmunity by targeting Aire.
Aire; DCs; CD4+T cells; T1D
Hepatitis B virus (HBV) causes acute and chronic hepatitis B (CHB). Due to its error-prone replication via reverse transcription, HBV can rapidly evolve variants that escape vaccination and/or become resistant to CHB treatment with nucleoside/nucleotide analogs (NAs). This is particularly problematic for the first generation NAs lamivudine and adefovir. Though now superseded by more potent NAs, both are still widely used. Furthermore, resistance against the older NAs can contribute to cross-resistance against more advanced NAs. For lack of feasible HBV infection systems, the biology of such variants is not well understood. From the recent discovery of Na+-taurocholate cotransporting polypeptide (NTCP) as an HBV receptor new in vitro infection systems are emerging, yet access to the required large amounts of virions, in particular variants, remains a limiting factor. Stably HBV producing cell lines address both issues by allowing to study intracellular viral replication and as a permanent source of defined virions. Accordingly, we generated a panel of new tetracycline regulated TetOFF HepG2 hepatoma cell lines which produce six lamivudine and adefovir resistance-associated and two vaccine escape variants of HBV as well as the model virus woolly monkey HBV (WMHBV). The cell line-borne viruses reproduced the expected NA resistance profiles and all were equally sensitive against a non-NA drug. The new cell lines should be valuable to investigate under standardized conditions HBV resistance and cross-resistance. With titers of secreted virions reaching >3x107 viral genome equivalents per ml they should also facilitate exploitation of the new in vitro infection systems.
Purpose: The aim of the present study was to investigate the effects of matrine on proliferation and apoptosis in human breast cancer MCF-7 cells and its relevant molecular mechanisms. Methods: Breast carcinoma cell line MCF-7 was cultured with series concentrations of Matrine in vitro. The proliferation and apoptosis of MCF-7 cells were investigated by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and Mitochondrial membrane potential (MMP) measurements. The expression levels of Bax and Bcl-2 proteins were detected by Annexin V/propidium iodide coupled staining. The morphological changes of MCF-7 cell were examined. Results: The inhibition rates of MCF-7 cells were 6.01%-37.01%, 7.56%-53.92%, and 10.86%-70.23% for 24, 48, and 72 hours after Matrine treatment, respectively. The proliferation of MCF-7 cells was significantly inhibited by Matrine administration, with a time and dose dependent manner. The rates apoptotic cells was between 4.17±0.25% and 19.63±0.17% in 0.25-2.0 mg/ml Matrine groups, which had significant increased compare with the control groups (1.10±0.08%, P<0.05). Meanwhile, increased Bax expression, but decreased Bcl-2 expression was observed in MCF-7 cell line. MMP were significantly decreased by Matrine treatment. Conclusions: Matrine significantly inhibited the growth and induced apoptosis in breast carcinoma MCF-7 cells, which is related to Bax, Bcl-2 signaling and MMP.
Matrine; breast cancer; proliferation; apoptosis; Bax; Bcl-2; mitochondrial
CD4+CD25+FoxP3+ regulatory T cells (Tregs) are increased in patients with chronic hepatitis C, which may contribute to the sustained suppression of hepatitis C virus (HCV)-specific T-cell responses and viral persistence in HCV-infected individuals. We postulated that HCV core protein (HCVc) directly contributes to the expansion of Tregs in HCV-infected patients, and we provide evidence to support this hypothesis in the report. Peripheral blood mononuclear cells (PBMCs) and sera were collected from 87 treatment-naïve chronic HCV-infected patients, CD4+CD25+ Tregs were measured by flow cytometry, and HCV RNA and HCVc levels were detected using qPCR and enzyme-linked immunosorbent assay (ELISA), respectively. CD4+, CD8+, CD4+CD25+ and CD4+CD25− T cells were purified from healthy donors and cultured with recombinant HCVc and Toll-like receptor (TLR) ligands. Flow cytometry was used to analyze cell proliferation, and ELISA was performed to measure cytokine production. In the 87 chronic HCV-infected patients, HCVc showed a significant correlation with HCV RNA and CD4+CD25+ Tregs. Mechanistic studies showed that HCVc, together with anti-CD3 antibody, augmented CD4+CD25+ Treg proliferation, but inhibited CD4+CD25− T-cell proliferation and IFN-γ production, in a dose-dependent and Treg-dependent manner. Moreover, unlike the TLR3 ligand (poly I:C) and the TLR4 ligand (lipopolysaccharide, LPS), the TLR2 ligand (lipoteichoic acid, LTA) and HCVc both inhibited TCR-induced CD4+ T-cell proliferation and IFN-γ secretion in a Treg-dependent manner. These data indicate that HCVc, like other TLR2 ligands, triggers CD4+CD25+ Treg activation and expansion to inhibit host immune responses, which may play a critical role in viral persistence in HCV-infected patients.
CD4+CD25+ regulatory T cells; HCV core; Toll-like receptor
Neurofibromatosis 1 (NF1) is a common disease that mainly affects the skin and peripheral nervous system, and is characterized by bony dysplasia. Primary congenital glaucoma (PCG) is a sight-threatening disease that can manifest as a prodrome of NF1, especially in newborn babies. We report a case of PCG with NF 1.
A 1-month-old boy presented with an enlarged right eyeball. An increased IOP and typical glaucomatous optic neuropathy were found, on the initial physical examination, a clinical diagnosis of primary congenital glaucoma (PCG) was made and a trabeculectomy with mitomycin C (MMC) therapy was subsequently performed. Three year later, the boy again presented with an even larger right eye and a gradually expanding left one. In addition to typical glaucomatous optic neuropathy, the boy also had multiple café au lait patches all over his body, megacephaly (head circumference = 60 cm; body weight = 14 kg; height = 93 cm) and remarkable facial features included swollen, soft upper eyelids and a flat, broad nose sphenoid wing dysplasia, eyelid thickening, bony orbit enlargement were found.
It is rare have both PCG and NF1, and PCG may be a prelude to NF1. Continuous follow-up should be advised and we should raise our awareness of the combined condition and to improve chances for an early diagnosis.
Primary congenital glaucoma; Neurofibromatosis 1; Diagnosis
QepA is one of the genes that confer quinolone resistance in bacteria. The aim of this study was to analyze the genetic structures of plasmids that carry a qepA3, a recently discovered allele of qepA in Enterobacteriaceae clinical isolates. 656 non-redundant Enterobacteriaceae clinical isolates were screened for the qepA3 gene and five isolates were identified to carry the gene. Plasmids were isolated from these isolates and were found to increase antibiotic resistance once the plasmids were transferred to Escherichia coli. These plasmids were subcloned and sequenced to analyze the genetic structures surrounding the qepA3 gene. The results showed that the five plasmids had different genetic structures; two of the qepA3-containning isolates had either the blaCTX-M-14 or blaTEM-12 gene instead of the blaTEM-1 gene. The structures of both pKP3764 and pECL3786 have not been previously described. In comparison with pHPA, there were a number of changes in DNA sequences up- and down-stream of the qepA3 gene. These findings provide better understanding of the genetic variations in qepA3 and would be useful for diagnosis and control of quinolone resistance in clinical settings.
plasmid-mediated quinolone resistance; QepA3 gene; recombinant plasmid; genetic structure; gene variation
We demonstrate a handheld multiphoton endomicroscope with 3.4 mm distal diameter that can repetitively image mouse colon in vivo. A 2D resonant MEMS mirror was developed to perform beam scanning in a Lissajous pattern. The instrument has an effective numerical aperture of 0.63, lateral and axial resolution of 2.03 and 9.02 μm, respectively, working distance of 60 μm, and image field-of-view of 300 × 300 μm2. Hoechst was injected intravenously in mice to stain cell nuclei. We were able to collect histology-like images in vivo at 5 frames/sec, and distinguish between normal and pre-malignant colonic epithelium.
(170.0170) Medical optics and biotechnology; (060.2350) Fiber optics imaging; (110.0110) Imaging systems; (190.4180) Multiphoton processes; (170.2150) Endoscopic imaging
Percutaneous vertebroplasty (PVP) has been demonstrated to be effective in the treatment of osteoporotic fracture. The bilateral pedicular approach is the most frequently used method. However, unilateral PVP is becoming increasingly more attractive for surgeons because of its numerous benefits, including lower radiation exposure, less tissue injury, and less bone cement leakage. The purpose of this study was to investigate the anatomical feasibility of unilateral PVP by exploring the differences in the puncture success rate of the unilateral pedicular approach among different lumbar segments, between men and women, and between the left and right sides.
Punctures were simulated on magnetic resonance imaging scans of 200 patients (100 men, 100 women) at a maximum angle via a pedicular approach. The distance between the entry point and the midline of the vertebral body, the maximum puncture angle, the puncture success value, and the puncture success rate were measured and compared among different lumbar levels, between the two sexes, and between the left and right sides.
The maximum puncture distance between the entry point and the midline gradually increased from L1 to L5, and the maximum puncture angle showed the same tendency from L1 to L5. The puncture success values for L3 and L4 were higher than those for the other lumbar levels (L1, 31.53 ± 34.45; L2, 42.15 ± 28.06; L3, 56.21 ± 18.30; L4, 56.20 ± 12.93; and L5, 48.01 ± 6.88). The puncture success rates varied from 69.5 to 98.0 % among the different lumbar levels; L3 and L4 were the two highest (L3, 95.5 %; L4, 98.0 %). There were significant differences in these measurements between men and women and between the left and right sides.
PVP with the unilateral puncture approach appears more likely to succeed at L3 to L5 than at L1 and L2. The unilateral approach might be more suitable for men than women at levels other than L5. Additionally, the left pedicular approach might be optimal for unilateral PVP procedures.
Pedicle; MRI; Unilateral PVP; Puncture; Radiation exposure
Pedicle screw placement in thoracic and lumbar spine is technically demanding and involves radiation exposure. Commercially available systems for pedicle screw insertion are expensive and cannot be widely used for those less-developed areas. The purpose of our study was to develop a simple guide device assisting pedicle screw placement and improving the accuracy in the operation. A simple guide device was developed with the aim of improving accuracy of pedicle screw technique based on anatomical structures of the spine. We retrospectively collected clinical data of 111 consecutive patients who received treatment of pedicle screw internal fixation between January 2013 and September 2014. In total, 518 screws were inserted by the same surgeon, among which 280 screws were implanted in 60 patients (33 males and 27 females) with conventional freehand technique and 238 screws were implanted in 51 patients (27 males and 24 females) using the guide device. According to postoperative CT evaluation, screws were classified into different grades and accuracy rates were compared between the two groups. A total of 518 screws were placed (238 in the guide group, 280 in the conventional group). No intra-operative or postoperative complications such as infection, vessel and nerve injuries occurred. After postoperative CT evaluation, 215 from guide group and 236 from the conventional group were classified in Grade 1. Only screws in Grade 1 were considered as accurate insertion. Thus, the accuracy rates were 84.3% for the conventional group and 90.3% for the guide group respectively. Through statistical test, there was significant difference in the accuracy rate between two groups. The simple guide device significantly improves the accuracy of pedicle screw placement. Combined with the advantage of cheapness, it can be widely used in spinal internal fixations, especially suitable for those inexperienced spine surgeons in less-developed areas.
Pedicle screw; guide device; radiation exposure; thoracolumbar spine; accuracy rate
Among individuals diagnosed with schizophrenia, approximately 20%–33% are recognized as treatment-resistant schizophrenia (TRS) patients. These TRS patients suffer more severely from the disease but struggle to benefit from existing antipsychotic treatments. A few recent studies suggested that schizophrenia may be caused by impaired synaptic plasticity that manifests as functional dysconnectivity in the brain, however, few of those studies focused on the functional connectivity changes in the brains of TRS groups. In this study, we compared the whole brain connectivity variations in TRS patients, their unaffected siblings, and healthy controls. Connectivity network features between and within the 116 automated anatomical labeling (AAL) brain regions were calculated and compared using maps created with three contrasts: patient vs. control, patient vs. sibling, and sibling vs. control. To evaluate the predictive power of the selected features, we performed a multivariate classification approach. We also evaluated the influence of six important clinical measures (e.g. age, education level) on the connectivity features. This study identified abnormal significant connectivity changes of three patterns in TRS patients and their unaffected siblings: 1) 69 patient-specific connectivity (PCN); 2) 102 shared connectivity (SCN); and 3) 457 unshared connectivity (UCN). While the first two patterns were widely reported by previous non-TRS specific studies, we were among the first to report widespread significant connectivity differences between TRS patient groups and their healthy sibling groups. Observations of this study may provide new insights for the understanding of the neurophysiological mechanisms of TRS.
•We first compared global functional connectivity in treatment-resistant schizophrenia and their unaffected siblings.•Widespread unshared significant functional connectivity in unaffected siblings of treatment-resistant schizophrenia•We studied the association of brain connectivity to clinical measures.
Schizophrenia; TRS; Brain plasticity; Functional connectivity; Sibling controls
Pathologists evaluate histology sectioned perpendicular to the tissue surface, or vertical cross-section. This orientation (XZ-plane) enables evaluation of mucosal differentiation in the basilar-to-luminal direction. Current endomicroscopes use a conventional (single axis) optical design.1 Imaging is limited to horizontal cross-sections (XY-plane) where the micro-anatomy is frequently similar across the field-of-view (FOV). In the dual axes configuration, light is delivered and collected off-axis, and images can be detected over a much larger range of intensities.2 Molecular images collected using fluorescence can improve specificity for disease detection and reveal functional properties about tissue.3 Proper interpretation of these images requires correlation with the micro-anatomy. We aim to demonstrate the simultaneous collection of two fluorescence images in vivo in vertical cross-sections using a dual axes confocal endomicroscope. An overlay of molecular and anatomical images from normal and dysplastic mouse colonic mucosa will be displayed in real time.
MicroRNA (miRNA)-153 (miR-153) has been considered as a novel tumor-related miRNA and is found to be significantly deregulated in human cancers. In this study, we found that the expression levels of miR-153 were obviously lower in gastric cancer tissues than those in matched adjacent nontumor tissues. Otherwise, miR-153 was expressed at significantly lower levels in aggressive tumor tissues. Clinical association analysis indicated that low expression of miR-153 was prominently correlated with poor prognostic features in gastric cancer. Furthermore, we demonstrated that the low expression of miR-153 was correlated with short 5-year survival of gastric cancer patients. Multivariate Cox regression analysis indicated that miR-153 was an independent prognostic marker in gastric cancer. Our in vitro studies showed that upregulation of miR-153 reduced cell migration and invasion in MKN-45 cells. Meanwhile, downregulation of miR-153 promoted SGC-7901 cell migration and invasion. An inverse correlation between miR-153 and SNAI1 expression was observed in gastric cancer tissues. In addition, upregulation of miR-153 reduced SNAI1 expression and subsequently suppressed epithelial–mesenchymal transition (EMT) with elevated expression of E-cadherin and reduced expression of vimentin in MKN-45 cells. Furthermore, downregulation of miR-153 increased SNAI1 expression and promoted EMT in SGC-7901 cells. In conclusion, miR-153 is an independent prognostic marker for predicting survival of gastric cancer patients and may promote gastric cancer cell migration and invasion, by inhibiting SNAI1-induced EMT.
miR-153; prognosis; SNAI1; EMT; tumor metastasis
This study aimed to introduce a novel mini-open pedicle screw fixation technique via Wiltse approach, and compared it with the traditional posterior open method. A total of 72 cases of single-segment thoracolumbar fractures without neurologic injury underwent pedicle screw fixation via two different approaches. Among them, 37 patients were treated using posterior open surgery, and 35 patients received mini-open operation via Wiltse approach. Crew placement accuracy rate, operative time, blood loss, postoperative drainage, postoperative hospitalization time, radiation exposure time, postoperative improvement in R value, Cobb's angle and visual analog scale (VAS) scores of the two methods were compared. There were no significant differences in the accuracy rate of pedicle screw placement, radiation exposure and postoperative R value and Cobb's angle improvement between the two groups. However, the mini-open method had obvious advantages over the conventional open method in operative time, blood loss, postoperative drainage, postoperative hospitalization time, and postoperative improvement in VAS. The mini-open pedicle screw technique could be applied in treatment of single-segment thoracolumbar fracture without neurologic injury and had advantages of less tissue trauma, short operative and rehabilitative time on the premise of guaranteed accuracy rate and no increased radiation exposure.
thoracolumbar fracture; pedicle screw; Mini-open; Wiltse approach; minimally invasive
High frequency large scanning angle electrostatically actuated microelectromechanical systems (MEMS) mirrors are used in a variety of applications involving fast optical scanning. A 1-D parametrically resonant torsional micromirror for use in biomedical imaging is analyzed here with respect to operation by duty-cycled square waves. Duty-cycled square wave excitation can have significant advantages for practical mirror regulation and/or control. The mirror’s nonlinear dynamics under such excitation is analyzed in a Hill’s equation form. This form is used to predict stability regions (the voltage-frequency relationship) of parametric resonance behavior over large scanning angles using iterative approximations for nonlinear capacitance behavior of the mirror. Numerical simulations are also performed to obtain the mirror’s frequency response over several voltages for various duty cycles. Frequency sweeps, stability results, and duty cycle trends from both analytical and simulation methods are compared with experimental results. Both analytical models and simulations show good agreement with experimental results over the range of duty cycled excitations tested. This paper discusses the implications of changing amplitude and phase with duty cycle for robust open-loop operation and future closed-loop operating strategies.
MEMS; micro-mirror; parametric resonance; Hill’s equation; nonlinear dynamics
Due to a lack of evidence, there is no consistent age of onset to define early onset (EO) versus later onset (LO) major depressive disorder (MDD). Fractional anisotropy (FA), derived from diffusion tensor imaging (DTI), has been widely used to study neuropsychiatric disorders by providing information about the brain circuitry, abnormalities of which might facilitate the delineation of EO versus LO MDD.
In this study, 61 pairs of untreated, non-elderly, first-episode MDD patients and healthy controls (HCs) aged 18–45 years old received DTI scans. The voxel-based analysis method (VBM), classification analysis, using the Statistical Package for the Social Sciences (SPSS), and regression analyses were used to determine abnormal FA clusters and their correlations with age of onset and clinical symptoms.
Classification analysis suggested in the best model that there were two subgroups of MDD patients, delineated by an age of onset of 30 years old, by which MDD patients could be divided into EO (18–29 years old) and LO (30–45 years old) groups. LO MDD was characterized by decreased FA, especially in the white matter (WM) of the fronto-occipital fasciculus and posterior limb of internal capsule, with a negative correlation with the severity of depressive symptoms; in marked contrast, EO MDD showed increased FA, especially in the WM of the corpus callosum, corticospinal midbrain and inferior fronto-occipital fasciculus, while FA of the WM near the midbrain had a positive correlation with the severity of depressive symptoms.
Specific abnormalities of the brain circuitry in EO vs. LO MDD were delineated by an age of onset of 30 years old, as demonstrated by distinct abnormal FA clusters with opposite correlations with clinical symptoms. This DTI study supported the evidence of an exact age for the delineation of MDD, which could have broad multidisciplinary importance.
Plasmacytoid dendritic cells (pDCs) are reported to be defective in HCV-infected patients, the mechanisms of which remain poorly understood. We isolated liver derived mononuclear cells (LMNCs) and pDCs from normal liver tissues of benign tumor dissections and liver transplant donors. Isolated pDCs and LMNCs were cultured with precoated HCV envelop protein E2 (HCV-E2) or anti-CD81 mAb in the presence of CpG-ODN. Our results show that cross-linking of CD81 by either HCV-E2 or anti-CD81 mAb inhibits IFN-α secretion in CpG-induced pDCs; down-regulates HLA-DR, CD80 and CD86 expression in pDCs; and suppresses CpG-ODN induced proliferation and survival of pDCs. The blockade of CD81 by soluble anti-CD81 antibody restores pDCs response to CpG-ODN. These results suggest that HCV E2 protein interacts with CD81 to inhibit pDC maturation, activation, and IFN-α production, and may thereby contribute to the impaired innate anti-viral immune response in HCV infection.
Plasmacytoid dendritic cells (pDCs); Hepatitis C virus envelop protein (HCV-E); CpG oligodeoxynucleotides (CpG-ODN); Toll-like receptor 9 (TLR9); Cross-linking