Sulfur-Doped Quintuple [9]Helicene with Azacorannulene as Core.

Herein, a hetero(S,N)-quintuple [9]helicene (SNQ9H) molecule with an azacorannulene core was synthesized, currently representing the highest hetero-helicene reported in the field of multiple [n]helicenes. X-ray crystallography indicated that SNQ9H includes not only a propeller-shaped conformer SNQ9H-1, but also an unforeseen quasi-propeller-shaped conformer SNQ9H-2. Different conformers were observed for the first time in multiple [n≥9]helicenes, likely owing to the doping of heteroatomic sulfurs in the helical skeletons. Remarkably, the ratio of SNQ9H-1 to SNQ9H-2 can be regulated in situ by the reaction temperature. Experimental studies on the photophysical and redox properties of SNQ9H and theoretical calculations clearly demonstrated that the electronic structures of SNQ9H depend on their molecular conformations. The strategy of introducing heteroatomic sulfurs into the helical skeleton may be useful in constructing various conformers of higher multiple [n]helicenes in the future.

Nitrogen-Embedded Quintuple [7]Helicene: A Helicene-Azacorannulene Hybrid with Strong Near-Infrared Fluorescence.

Herein, a nitrogen-embedded quintuple [7]helicene (N-Q7H) with an azapentabenzocorannulene core, which can be considered to be a helicene/azacorannulene hybrid π-system, was synthesized from azapentabenzocorannulene in a three-step process. N-Q7H is the first example of a multiple helicene with an azabuckybowl core. Single-crystal X-ray diffractometry unambiguously confirmed the structure of the propeller-shaped hybrid π-system. Owing to nitrogen-atom doping in the multiple helicenes and effective hybridization between the helicene and azacorannulene, N-Q7H exhibits considerably redshifted absorption and emission (yellow-to-green color change and green-to-near-infrared fluorescence change) relative to the azapentabenzocorannulene core. The broad absorption from the ultraviolet-visible to the NIR region is ascribable to the allowed transition between the highest occupied molecular orbital and the lowest unoccupied molecular orbital after symmetry breaking, as revealed by density functional theory calculations. Compared to previous propeller-shaped multiple helicenes with corannulene or hexabenzocoronene (etc.) as cores, N-Q7H demonstrates a significantly higher NIR fluorescence quantum efficiency of 28%. Additionally, the chiral-resolution and redox properties of N-Q7H were investigated. The excellent photophysical and inherent chiral properties of N-Q7H suggest that azapentabenzocorannulene can be used as an outstanding nitrogen-embedded core to construct novel multiple helicenes with wide application potential, including as NIR fluorescent bio-probes.

C2-C3 Anterior Cervical Diskectomy and Fusion for Hangman's Fractures with C2 Posterior Dislocation: Technical Notes.

BACKGROUND: The overwhelming majority of hangman's fractures cause anterior dislocation of C2. Hangman's fracture with C2 posterior dislocation is extremely rare; only 1 pediatric case was reported in 2018 to date. This kind of injury cannot be cataloged using current classification schemes, and no established treatment recommendations exist. The purpose of this article is to report a rare case of a hangman's fracture with C2 posterior dislocation, which does not fit into existing classification systems and discuss management technical notes to avoid pitfalls. METHODS: We describe this case, review relevant literature, and share our experience. RESULTS: A 31-year-old male sustained a hangman's fracture with C2 posterior dislocation after he fell into a 50-cm deep roadside ditch when riding a motorcycle. Radiograph and computed tomography on admission showed fractures through both pars of C2 and C2 posterior dislocation. Magnetic resonance imaging on admission showed high T2-weighted signal intensity of cervical spinal cord and compression of the cervical spinal cord by posterior dislocation of the C2 vertebral body. A C2-3 anterior cervical diskectomy and fusion was performed. At 6 months after operation, bony fusion was achieved and magnetic resonance imaging showed the T2-weighted signal hyperintensity of cervical spinal cord before surgery disappeared. CONCLUSIONS: C2-C3 anterior cervical diskectomy and fusion is recommended for hangman's fractures with C2 posterior dislocation. Traction before surgery is not recommended.

Sulfonyl-containing phenyl-pyrrolyl pentane analogues: Novel non-secosteroidal vitamin D receptor modulators with favorable physicochemical properties, pharmacokinetic properties and anti-tumor activity.

Modulating the vitamin D receptor (VDR) is an effective way to treat for cancer. We previously reported a potent non-secosteroidal VDR modulator (sw-22) with modest anti-tumor activity, which could be due to its undesirable physicochemical and pharmacokinetic properties. In this study, we investigated the structure-activity and structure-property relationships around the 2'-hydroxyl group of sw-22 to improve the physicochemical properties, pharmacokinetic properties and anti-tumor activity. Compounds 19a and 27b, the potent non-secosteroidal VDR modulators, were identified as the most effective molecules in inhibiting the proliferation of three cancer cell lines, particularly breast cancer cells, with a low IC50 via the distribution of cell cycle and induction of apoptosis by stimulating the expression of p21, p27 and Bax. Further investigation revealed that 19a and 27b possessed favorable rat microsomal metabolic stability (2.22 and 2.3 times, respectively, more stable than sw-22), solubility (43.9 and 50.2 times, respectively, more soluble than sw-22) and in vivo pharmacokinetic properties. In addition, 19a and 27b showed excellent in vivo anti-tumor activity without cause hypercalcemia, which is the main side effect of marketed VDR modulators. In summary, the favorable physicochemical properties, pharmacokinetic properties and anti-tumor activity of 19a and 27b highlight their potential therapeutic applications in cancer treatment.

Calcification of the intervertebral disc and ossification of posterior longitudinal ligament in children.

BACKGROUND: IDC in children, first reported by Baron in 1924, is very rare. OPLL of the cervical spine mainly affect people ages 50-70 years. The coexistence of IDC and OPLL in children is very rare, only six cases with 3 to 24 months' follow-up were reported to date. CASE PRESENTATION: A 6-year-old boy presented with complains of neck pain at July 2007. The boy was treated by conservative treatment and observed up for 9 years. Neck pain greatly improved after a one-month conservative treatment and never recur. Laboratory tests revealed elevated ESR and CRP at admission and found nothing abnormal at 19-month and 9-year follow-up. Computed tomography and magnetic resonance imaging revealed IDC at C2/3, C3/4 and OPLL at C3/4 at admission and found minor calcification at C2/3 remained but calcification at C3/4 and OPLL at C3/4 completely disappeared at 19-month and 9-year follow-up. Nineteen months after initial diagnosis, restoration of T2-weighted signal intensity of C2/3 and C3/4 discs was observed through MRI. Loss of T2-weighted signal intensity of C2/3 disc and decrease of T2-weighted signal intensity of C3/4 disc was observed at 9-year follow-up. CONCLUSIONS: IDC with OPLL in children is very rare. Conservative treatments are recommended with affirmative short-term and long-term clinical effects. More intensive observation with long-term follow-ups may be needed to warrant the clinical effects.

Beagle sciatic nerve regeneration across a 30 mm defect bridged by chitosan/PGA artificial nerve grafts.

Longitudinally oriented microstructures are essential for a nerve scaffold to promote the significant regeneration of injured peripheral axons across nerve gaps. In the current study, we present a novel nerve-guiding collagen-chitosan (CCH) scaffold that facilitated the repair of 30 mm-long sciatic nerve defects in beagles. The CCH scaffolds were observed with a scanning electron microscope. Eighteen beagles were equally divided into CCH group, autograft group and non-graft group. The posture and gait of each dog was recorded at 12 and 24 weeks after surgery. Electrophysiological tests, Fluoro-Gold retrograde tracing test, Histological assessment of gastrocnemius and immunofluorescent staining of nerve regeneration were performed. Our investigation of regenerated sciatic nerves indicated that a CCH scaffold strongly supported directed axon regeneration in a manner similar to that achieved by autologous nerve transplantation. In vivo animal experiments showed that the CCH scaffold achieved nerve regeneration and functional recovery equivalent to that achieved by an autograft but without requiring the exogenous delivery of regenerative agents or cell transplantation. We conclude that CCH nerve guides show great promise as a method for repairing peripheral nerve defects.

Design, synthesis and biological evaluation of non-secosteriodal vitamin D receptor ligand bearing double side chain for the treatment of chronic pancreatitis.

Chronic pancreatitis (CP) is a serious disease that characterized by the progressive replacement of functional pancreas tissue by fibrotic tissue. Vitamin D receptor (VDR) plays a critical role in the development of CP, since it inhibits excessive deposition of extracellular matrix (ECM) in activated pancreatic stellate cells (PSCs). Herein, a novel series of non-secosteriodal VDR ligands were designed and synthesized, and their VDR affinity and anti-fibrosis activity were evaluated. The identification of the potent compound 9c was found over structural optimization, which inhibited ECM deposition and fibrotic gene expression in the western blot and qPCR assays, respectively. Further investigation revealed that compound 9c inhibited pancreatic fibrosis in vivo without increase on serum calcium, which could cause hypercalcemia. These results provide novel insight in possible drug discovery for the treatment of CP using non-secosteroidal VDR modulators.

Biomechanical characterization of a novel ring connector for sutureless aortic anastomosis.

The surgical treatment for aortic diseases remains a challenge for any cardiac surgeon. The use of sutureless ring connector in aortic anastomosis can simplify the procedure and shorten anastomosis time. Therefore, we developed a novel device for sutureless aortic anastomosis. A series of experiments were carried out for tensile and leakproof-capacity assessments to verify the feasibility of the ring connector by using fresh swine aorta samples. In in vivo test, the ring connector was implanted in 6 swine with follow-up of 6 months. Radiographic and pathological studies of the aorta were performed. In the tensile tests, the strength was 32.7±5.9 Newton (N) in the sutureless anastomosis group, compared with 73.3±12.5 N in the control group by traditional manual suture. In the leakproof-capacity assessment, no sign of either leakage or bursting was evident at 280 mmHg of internal pressure in the aorta samples. In in vivo tests, it took 9.47±0.3 minutes for the sutureless anastomosis, compared with 15.58±1.39 minutes for hand-sewn suturing. Insertion was easy and rapid. Radiographic and pathological studies were performed at first month, third month and sixth month after surgery, each time obtained from the two swine, showed patency of the anastomosis and no signs of stenosis, blood leakage, migration or pseudoaneurysm formation, except one paralyzed swine developed of thrombo-occlusion at the site of the sutureless anastomosis. The result indicates that this novel ring connector offers considerable promise for sutureless aortic anastomosis.

Role of miR-155 in the regulation of MMP-16 expression in intervertebral disc degeneration.

The molecular mechanisms of intervertebral disc degeneration (IDD) remain elusive. We found that miR-155 is down-regulated in degenerative nucleus pulposus (NP), and more severe degeneration is correlated with higher matrix metallopeptidase 16 (MMP-16) expression. MMP-16 also degraded matrix aggrecan. Here, we addressed the in vivo miR-155-mediated pathological impact on IDD using a classic puncture mouse model. Lentiviral upregulated-miR-155 or downregulated-miR-155 was transduced into the discs of C57 mice, which was validated by real-time polymerase chain reaction (real-time PCR) and in situ hybridization. Immunohistochemistry and western blotting revealed that up-regulation of miR-155 resulted in down-regulation of MMP-16 and an increase in aggrecan and collagen type II in mouse NP; whereas, down-regulation of miR-155 resulted in up-regulation of MMP-16 and a decrease in aggrecan in mouse NP. Radiographic and histological analysis showed that the up-regulation of miR-155 attenuated IDD, while down-regulation of miR-155 resulted in the deterioration of IDD. These findings indicate that decreased miR-155 contributed to the up-regulation of MMP-16 in vivo, and MMP-16 further degraded aggrecan and collagen type II, leading to the dehydration and degeneration of discs. Our findings revealed a therapeutic role for miR-155 in IDD. © 2017 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:1323-1334, 2017.

Calcification of the intervertebral disc and posterior longitudinal ligament in children.

STUDY DESIGN: Case report. OBJECTIVE: To report the clinical features, radiographic findings, treatments, and results of 2 children with cervical intervertebral disc calcification combined with ossification of the posterior longitudinal ligament (OPLL). SUMMARY OF BACKGROUND DATA: The calcification of the intervertebral disc, which is more frequent in males with predominant localization to cervical spine, was first reported by Baron in 1924. OPLL of the cervical spine, which is found approximately in the 5th to 7th decade of life, is a disease-causing spinal canal stenosis and spinal cord compression. The etiologies of these 2 diseases still remain unclear. METHODS: An 8-year-old girl presented with progressive neck pain and complained of weakness and numbness of the upper left extremity, and a 6-year-old boy presented with complains of neck pain. X-ray, computed tomography, and magnetic resonance imaging findings of 2 patients confirmed the presence of cervical intervertebral disc calcification combined with OPLL. RESULTS: Two children were treated using conservative treatment. The girl was observed up for 2 years and the boy was observed up for 18 months, respectively. Computed tomography and magnetic resonance imaging revealed that cervical intervertebral disc calcification and OPLL at the C6/7 (case 1) and C3/4 (case 2) level have disappeared completely, only a small calcification at the C2/3 intervertebral disc remained in the second case and both of them were asymptomatic. CONCLUSIONS: Cervical intervertebral disc calcification combined with OPLL was rarely observed in children. Conservative management was carried out and the patients had a full recovery. Our experience suggests that the conservative treatment is an acceptable method.

Ghrelin stimulates proliferation of human osteoblastic TE85 cells via NO/cGMP signaling pathway.

Ghrelin regulates bone formation and osteoblast proliferation, but the detailed signaling pathway for its action on osteoblasts remains unclear. In human osteoblastic TE85 cells, we observed the effects and intracellular signaling pathway of ghrelin on cell proliferation using BrdU incorporation method. Ghrelin, at 10(-10)-10(-8) M concentration, significantly increased BrdU incorporation into TE85 cells. The action of ghrelin was inhibited by D: -Lys3-GHRP-6, a selective antagonist of GHS-R. Nitric oxide (NO) scavenger hemoglobin and the NO synthase inhibitor NAME eliminated the stimulatory action of ghrelin on proliferation, while NO donor SNAP and NO synthase substrate L-AME stimulated proliferation of osteoblastic TE85 cells. The cGMP analogue, 8-Br-cGMP, stimulated TE85 cell proliferation, and ghrelin did not enhance proliferation in the presence of 8-Br-cGMP. Inhibition of cGMP production by the guanylate cyclase inhibitor prevented ghrelin-induced osteoblastic TE85 cell proliferation. In conclusion, ghrelin stimulates proliferation of human osteoblastic TE85 cells via intracellular NO/cGMP signaling pathway.