An innovative adjustable prone positioning frame for treatment of severe kyphosis secondary to ankylosing spondylitis with two-level osteotomy.

PURPOSE: This study aims to introduce an innovative adjustable prone positioning frame (APPF) and explore its feasibility and safety for treatment of severe kyphosis secondary to ankylosing spondylitis (AS) with two-level osteotomy. METHODS: A retrospective, non-controlled study was conducted to illustrate the process where 13 patients diagnosed with severe kyphosis secondary to AS received operations on the APPF. Parameters of chin brow vertical angle (CBVA), global kyphosis (GK), thoracolumbar kyphosis (TLK), lumbar lordosis (LL) and sagittal vertical axis (SVA) were measured. Positioning time, operation time, intraoperative blood loss ahd complications were also determined. The Scoliosis Research Society outcomes instrument (SRS-22) was applied for clinical assessment. RESULTS: All patients were placed on the APPF successfully with the positioning time of 2.92 ± 0.76 min, received operation with 457.00 ± 88.04 min and had blood loss of 2330.77 ± 1423.25 ml. Four cases experienced pain due to tensional skin of the abdomen and one case suffered cerebrospinal fluid leakage postoperatively, but these patients were all cured conservatively. No neurological complications were observed, although sagittal translation occurred in four patients. Significant improvements were detected in CBVA, GK, TLK, LL and SVA postoperatively (P < 0.05), but no significant difference was observed between postoperation and the final follow-up (P > 0.05). The SRS-22 scores at 2 years after operation were significantly higher than those before operation (P < 0.05). CONCLUSION: The innovative APPF provided great convenience to place patients with severe kyphosis secondary to AS in a prone position. Performing two-level osteotomy with the aid of APPF is safe, feasible and effective.

Surgical management of the fractures of axis body: indications and surgical strategy.

PURPOSE: The axis body fractures are relatively uncommon and have a variety of presentations. Surgical management to them has been only reported as case reports or included as a minor part of clinical management. The objective of this study is to summarize the indications for surgery and report the clinical outcome of surgical treatment based on different fracture patterns. METHODS: A retrospective analysis of 28 consecutive patients presenting with the axis body fractures was undertaken. The indications for surgical treatment were defined as: (1) fractures associated with instability of adjacent joints; (2) irreducible displaced superior articular facet fracture; (3) fractures resulting in spinal cord compression. The fractures were classified as sagittal, coronal, transverse and lateral mass fracture. One of the following surgical procedures was applied according to the fracture pattern: posterior C1-C2 pedicle screws fixation and fusion (I); posterior C1-C3 screws fixation and fusion (II); posterior osteosynthesis with C2 transpedicular half-thread lag screws (III). RESULTS: 13 patients were successfully managed operatively. Two transverse and two unilateral lateral mass fractures were treated with surgical procedure I, five sagittal fractures with II, four coronal fractures with III. Complications of malposition of screws and neurologic deficit did not occur during operation. Satisfactory reduction and bony union were demonstrated on postoperative radiographics. CONCLUSIONS: Conservative treatment is still advocated as primary management for most axis body fractures. But for patients with obvious adjacent joints instability or irreducible displaced superior articular facet fracture, surgical intervention based on the different fracture pattern is necessary.

Safety and risk factors of TINAVI robot-assisted percutaneous pedicle screw placement in spinal surgery.

OBJECTIVE: To determine the rates and risk factors of pedicle screw placement accuracy and the proximal facet joint violation (FJV) using TINAVI robot-assisted technique. METHODS: Patients with thoracolumbar fractures or degenerative diseases were retrospectively recruited from June 2018 and June 2020. The pedicle penetration and proximal FJV were compared in different instrumental levels to identify the safe and risk segments during insertion. Moreover, the factors were also assessed using univariate and multivariate analyses. RESULTS: A total of 72 patients with 332 pedicle screws were included in the current study. The optimal and clinically acceptable screw positions were 85.8% and 93.4%. Of the 332 screws concerning the intra-pedicular accuracy, 285 screws (85.8%) were evaluated as Grade A according to the Gertzbein and Robbins scale, with the remaining 25 (7.6%), 10 (3.0%), 6 (1.8%), and 6 screws (1.8%) as Grades B, C, D, and E. Moreover, in terms of the proximal FJV, 255 screws (76.8%) screws were assessed as Grade 0 according to the Babu scale, with the remaining 34 (10.3%), 22 (6.6%), and 21 screws (6.3%) as Grades 1, 2, and 3. Furthermore, the univariate analysis showed significantly higher rate of penetration for patients with age < 61 years old, sex of female, thoracolumbar insertion, shorter distance from skin to insertion point, and smaller facet angle. Meanwhile, the patients with the sex of female, BMI < 25.9, grade I spondylolisthesis, lumbosacral insertion, longer distance from skin to insertion point, and larger facet angle had a significantly higher rate of proximal FJV. The outcomes of multivariate analyses showed that sex of male (adjusted OR 0.320, 95% CI 0.140-0.732; p = 0.007), facet angle ≥ 45° (adjusted OR 0.266, 95% CI 0.090-0.786; p = 0.017), distance from skin to insertion point ≥ 4.5 cm (adjusted OR 0.342, 95% CI 0.134-0.868; p = 0.024), and lumbosacral instrumentation (adjusted OR 0.227, 95% CI 0.091-0.566; p = 0.001) were independently associated with intra-pedicular accuracy; the L5 insertion (adjusted OR 2.020, 95% CI 1.084-3.766; p = 0.027) and facet angle ≥ 45° (adjusted OR 1.839, 95% CI 1.026-3.298; p = 0.041) were independently associated with the proximal FJV. CONCLUSION: TINAVI robot-assisted technique was associated with a high rate of pedicle screw placement and a low rate of proximal FJV. This new technique showed a safe and precise performance for pedicle screw placement in spinal surgery. Facet angle ≥ 45° is independently associated with both the intra-pedicular accuracy and proximal FJV.

Overexpression of the human ubiquitin E3 ligase CUL4A alleviates hypoxia-reoxygenation injury in pheochromocytoma (PC12) cells.

The ubiquitin E3 ligase CUL4A plays important roles in diverse cellular processes including carcinogenesis and proliferation. It has been reported that the expression of CUL4A can be induced by hypoxic-ischemic injury. However, the effect of elevated expression of CUL4A on hypoxia-reoxygenation injury is currently unclear. In this study, human CUL4A (hCUL4A) was expressed in rat pheochromocytoma (PC12) cells using adenoviral vector-mediated gene transfer, and the effects of hCUL4A expression on hypoxia-reoxygenation injury were investigated. In PC12 cells subjected to hypoxia and reoxygenation, we found that hCUL4A suppresses apoptosis and DNA damage by regulating apoptosis-related proteins and cell cycle regulators (Bcl-2, caspase-3, p53 and p27); consequently, hCUL4A promotes cell survival. Taken together, our results reveal the beneficial effects of hCUL4A in PC12 cells upon hypoxia-reoxygenation injury.

The Rates and Risk Factors of Intra-Pedicular Accuracy and Proximal Facet Joint Violation for Single-Level Degenerative Lumbar Diseases: Cortical Bone Trajectory Versus Traditional Trajectory Pedicle Screw.

STUDY DESIGN: A retrospective study. OBJECTIVE: To compare the accuracy of pedicle screw placement and proximal facet joint violation (FJV) in single-level degenerative lumbar diseases using cortical bone trajectory (CBT) and traditional trajectory (TT) techniques, and analyze their possible risk factors. SUMMARY OF BACKGROUND DATA: CBT screws have been utilized increasingly to improve cortical bone contact to prevent screw pullout and reduce approach-related morbidity. However, the studies on intra-pedicular accuracy and proximal FJV between the two methods are rare. METHODS: A total of 40 patients who required single-level instruments were included in the retrospective study treated with the CBT-TLIF and the TT-TLIF at a 1:1 ratio from March 2019 to August 2020. The radiographic outcomes were the intra-pedicular accuracy and proximal FJV. Moreover, the possible risk factors were assessed using bivariate and multivariate analyses. RESULTS: As for the intra-pedicular accuracy, 73 screws (91.3%) were classified as grade A, 7 screws (8.7%) classified as grade B in the CBT group. A total of 71 screws (88.8%) were graded A with remaining 8 screws (10.0%) graded B and 1 screw (1.2%) graded C in the TT group. The proportion of optimal and clinically acceptable screw positions in the two groups were not significantly different (P > 0.05). In addition, the rate of proximal FJV in CBT approach (8.3%) was significantly lower than that in the TT approach (35.0%) (P < 0.001). Multivariate analysis showed the TT insertion approach and facet angle ≥45° were the independent risk factors for proximal FJV, but no factors above affected intra-pedicular accuracy. CONCLUSION: Compared with the TT approach in TLIF, the CBT approach showed similar intra-pedicular accuracy and remarkable superiority in proximal facet joint protection. Facet angle ≥45° is the independent risk factors for proximal FJV.Level of Evidence: 2.

Genome-wide scanning reveals complex etiology of oculo-auriculo-vertebral spectrum.

Oculo-auriculo-vertebral spectrum (OAVS) is a common developmental disorder involving first and second pharyngeal arches. Although some family cases and such patients showing chromosomal aberrations suggest that OAVS have a genetic basis, no consistent genetic defects have been recorded at present time. Thus, we conducted genetic studies of a three-generation family with five OAVS patients to identify a causative variant for OAVS. Cytogenetic studies revealed those family members had a normal karyotype and no causative mutations were founded in SALL1 and TCOF1, which known to be responsible for two other syndromes that have clinical overlapping with OAVS. Genotyping with commercially available BeadChips was performed on 13 individuals in the same family, showing no significant difference between the affected and normal members in terms of copy number variations (CNVs) in either number or size and no definitive causative CNV. A total of 8,224 informative autosomal SNPs that are evenly distributed throughout the genome were selected for both parametric and non-parametric linkage analysis. Significant negative LOD scores were obtained for the reported OAVS locus, providing further evidence for genetic heterogeneity of this complex disorder. The highest LOD score of 1.60 was noted on chromosome 15q26.2-q26.3 showing a potential linkage to this locus. The variable phenotypes of the affected members and the failure to identify a causative variant indicate that a complex etiology may be present even in a consanguineous family, which makes it more challenging to ascertain the cause of OAVS in further analysis.

Antioxidant Nanotherapies for the Treatment of Inflammatory Diseases.

Reactive oxygen species (ROS) are essential in regulating various physiological functions. However, overproduction of ROS is implicated in the pathogenesis of various inflammatory diseases. Antioxidant therapy has thus represented an effective strategy for the treatment of oxidative stress relevant inflammatory diseases. Conventional anti-oxidative agents showed limited in vivo effects owing to their non-specific distribution and low retention in disease sites. Over the past decades, significant achievements have been made in the development of antioxidant nanotherapies that exhibit multiple advantages such as excellent pharmacokinetics, stable anti-oxidative activity, and intrinsic ROS-scavenging properties. This review provides a comprehensive overview on recent advances in antioxidant nanotherapies, including ROS-scavenging inorganic nanoparticles, organic nanoparticles with intrinsic antioxidant activity, and drug-loaded anti-oxidant nanoparticles. We highlight the biomedical applications of antioxidant nanotherapies in the treatment of different inflammatory diseases, with an emphasis on inflammatory bowel disease, cardiovascular disease, and brain diseases. Current challenges and future perspectives to promote clinical translation of antioxidant nanotherapies are also briefly discussed.

[Recent advances in treatment of glial scar-induced inhibition of nerve regeneration].

Glial scar formed by central nervous system (CNS) injury is the main inhibitory barrier of nerve regeneration. How to promote axonal regeneration after injury,how to accelerate neural network reconstruction and how to improve brain function recovery have become a hot problem to be solved in the field of neuroscience. This article focuses on the recent advances of therapeutic strategies for axonal regeneration.

Rescue of cognitive deficits in APP/PS1 mice by accelerating the aggregation of ß-amyloid peptide.

BACKGROUND: Brain amyloid deposition is one of the main pathological characteristics of Alzheimer's disease (AD). Soluble oligomers formed during the process that causes ß-amyloid (Aß) to aggregate into plaques are considered to have major neurotoxicity. Currently, drug development for the treatment of Alzheimer's disease has encountered serious difficulties. Our newly proposed solution is to accelerate the aggregation of Aß to reduce the amount of cytotoxic Aß oligomers in brain tissue. This strategy differs from the existing strategy of reducing the total Aß content and the number of amyloid plaques. METHOD: In this study, we screened a small library and found that a flavonoid compound (ZGM1) promoted the aggregation of ß-amyloid (Aß). We further verified the binding of ZGM1 to Aß42 using a microscale thermophoresis (MST) assay. Subsequently, we used dot blotting (DB), transmission electron microscopy (TEM), and thioflavin T fluorescence (ThT) measurements to study the aggregation of Aß under the influence of ZGM1. By using cell experiments, we determined whether ZGM1 can inhibit the cytotoxicity of Aß. Finally, we studied the protective effects of ZGM1 on cognitive function in APPswe/PS1 mice via behavioral experiments and measured the number of plaques in the mouse brain by thioflavin staining. RESULTS: ZGM1 can bind with Aß directly and mediate a new Aß assembly process to form reticular aggregates and reduce the amount of Aß oligomers. Animal experiments showed that ZGM1 can significantly improve cognitive dysfunction and that Aß plaque deposition in the brain tissue of mice in the drug-administered group was significantly increased. CONCLUSION: Our research suggests that promoting Aß aggregation is a promising treatment method for AD and deserves further investigation.

Posterior osteosynthesis with monoaxial lateral mass screw-rod system for unstable C1 burst fractures.

BACKGROUND CONTEXT: Surgical treatment for unstable atlas fractures has evolved in recent decades from C1-C2 or C0-C2 fusion to motion-preservation techniques of open reduction and internal fixation (ORIF). However, regardless of a transoral or a posterior approach, the reduction is still not satisfactory. PURPOSE: The article describes and evaluates a new technique for treating unstable atlas fractures by using a monoaxial screw-rod system. STUDY DESIGN: This is a retrospective study. PATIENT SAMPLE: The sample includes adult patients with unstable C1 fractures treated with a posterior monoaxial screw-rod system. OUTCOME MEASURES: The outcome measures included a visual analog pain scale, radiographic reduction (lateral mass displacement [LMD]), maintenance of reduction, C1-C2 instability (anterior atlantodens interval), and complications. MATERIALS AND METHODS: From August 2013 to May 2016, nine consecutive patients with unstable atlas fractures were retrospectively reviewed. All patients were treated with posterior ORIF by using a monoaxial screw-rod system. The medical records and the preoperative and postoperative radiographs were reviewed. Preoperative and postoperative computed tomography scans were used to specify the fracture types and to assess the reduction. RESULTS: All nine patients with a mean age of 50.3 years successfully underwent surgery with this technique, and a follow-up of 17.4±9.3 months was performed. Transverse atlantal ligament (TAL) injury was found in eight of the nine patients: one of type I and seven of type II. The preoperative LMD averaged 7.0±2.2 mm and was restored completely after surgery; all the fractures achieved bony healing without loss of reduction or implant failure. None of the patients had complications of neurologic deficit, vertebral artery injury, or wound infection associated with the surgical procedure. Two patients complained of greater occipital nerve neuralgia after the operation, which gradually disappeared in 1 month. All patients had a well-preserved range of motion of the upper cervical spine at the final follow-up. CONCLUSIONS: Posterior osteosynthesis with a monoaxial screw-rod system is capable of an almost anatomical reduction for the unstable atlas fractures. The TAL incompetence may not be a contraindication to ORIF for C1 fractures, but the long-term effect of C1-C2 instability remains to be further investigated.

New vertebral fractures after osteoporotic vertebral compression fracture between balloon kyphoplasty and nonsurgical treatment PRISMA.

BACKGROUND: Because of aging of population, osteoporotic vertebral compression fracture (OVCF) appears an increasing incidence rate. Conservative therapy (CT) and balloon kyphoplasty (BKP) have been used to treat OVCFs. However, an increase in new vertebral compression fractures at nontreated levels following BKP is of concern. It is still not clear whether new fractures were a result of BKP and the purpose of this meta-analysis was to evaluate the new fractures risk after BKP compared with CT. METHODS: An exhaustive literature search of PubMed, EMBASE, and the Cochrane Library was conducted to identify randomized controlled trials and prospective nonrandomized controlled study that compared BKP with CT for patients suffering OVCF. A random-effect model was used. Results were reported as standardized mean difference or risk ratio with 95% confidence interval. RESULTS: Twelve studies were included and there was no significant difference in total new fractures (P = .33) and adjacent fractures (P = .83) between 2 treatments. Subgroup analyses did not demonstrate significant differences in follow-up period, mean age, anti-osteoporosis therapy, and the proportion of women. CONCLUSION: Our systematic review revealed that an increased risk of fracture of vertebral bodies was not associated with BKP compared with CT.

Biomechanical Fixation Properties of the Cortical Bone Trajectory in the Osteoporotic Lumbar Spine.

OBJECTIVE: Selecting optimal strategies for improving fixation in osteoporotic lumbar spine is an important issue in clinical research. Cortical bone trajectory (CBT) screws have been proven to enhance screw pullout strength, but biomechanical efficacy of these screws remains understudied. The aim of this study was to evaluate biomechanical efficacy of CBT screws in osteoporotic lumbar spine. METHODS: Thirty-one vertebrae from 14 cadaveric lumbar spines were obtained. All specimens were measured by computed tomography; the diameter of pedicles, excluding those of vertebral bodies with very small pedicle developments, was calculated. After measuring bone mineral density, the CBT screw was randomly inserted into 1 side, and the traditional trajectory (TT) screw was inserted into the contralateral side. Maximum insertional torque was recorded after screw insertion. Of vertebrae, 21 were subjected to pullout testing at a rate of 5 mm/minute, and 10 were subjected to cyclic fatigue testing. Each construct was loaded until exceeding 5 mm. RESULTS: Average bone mineral density was 0.567 ± 0.101 g/cm2. CBT screws had higher maximum insertional torque (degrees of freedom = 30, t = 5.78, P < 0.001, 0.333 N-m vs. 0.188 N-m) and higher axial pullout strength (degrees of freedom = 20, t = 7.41, P < 0.001, 394 N vs. 241 N) than TT screws. Increased bone mineral density was not significantly associated with higher pullout load. Compared with TT screws, CBT screws showed better resistance to fatigue testing and required more cycles to exceed 5 mm (degrees of freedom = 9, t = 5.62, P < 0.001, 6161 cycles vs. 3639 cycles). Failure load for displacing screws was also significantly greater for CBT screws than for TT screws (degrees of freedom = 9, t = 5.75, P < 0.001, 443 N vs. 317 N). CONCLUSIONS: CBT screws had better biomechanical fixation in osteoporotic lumbar spine compared with standard pedicle screws.

Indomethacin-loaded polymeric nanocarriers based on amphiphilic polyphosphazenes with poly (N-isopropylacrylamide) and ethyl tryptophan as side groups: Preparation, in vitro and in vivo evaluation.

The effects of copolymer composition, drug structure and initial drug feed on drug loading of polymeric micelles based on amphiphilic polyphosphazenes were investigated. It was found that the drug loading capacity of micelles based on this type of amphiphilic copolymers was mainly determined by copolymer composition and the chemical structure of drug. In addition to the compatibility between drug and micellar core, hydrogen bonding interaction between drug and hydrophilic corona may significantly influence drug loading as well. In vitro drug release in 0.1 M PBS (pH 7.4) suggested that indomethacin (IND) in the micelles was released through Fickian diffusion, and no significant difference in release rate was observed for micelles based on copolymers with various EtTrp content. Compared with in vitro IND release profile, in vivo pharmacokinetic study after subcutaneous administration provides a more sustained release behavior. Additionally, in comparison with free drug solution at the same dose, IND concentration in rat plasma showed a prolonged retention when the drug was delivered through polymeric micelles. In vivo pharmacodynamic study based on both carrageenan-induced acute and complete Freund's adjuvant-induced adjuvant arthritis model indicated that sustained therapeutic efficacy could be achieved through intraarticular injection of IND-loaded micelles. Most importantly, local delivery of IND can avoid the severe gastrointestinal stimulation, which was frequently associated with oral administration.

Thermally responsive polymeric micelles self-assembled by amphiphilic polyphosphazene with poly(N-isopropylacrylamide) and ethyl glycinate as side groups: polymer synthesis, characterization, and in vitro drug release study.

Thermally responsive amphiphilic poly(N-isopropylacrylamide) (PNIPAm)-grafted-polyphosphazene (PNIPAm-g-PPP) was synthesized by stepwise cosubstitution of chlorine atoms on polymer backbones with amino-terminated NIPAm oligomers and ethyl glycinate (GlyEt). Polymer structure was confirmed by FT-IR, (1)H NMR, elemental analysis, and GPC. The thermosensitivity of PNIPAm-g-PPP aqueous solution was investigated by turbidity method. The lower critical solution temperature (LCST) of PNIPAm-g-PPP was observed to be approximately 30 degrees C in water, while it was 24 degrees C in 0.1M PBS (pH 7.4). Micellization behavior of PNIPAm-g-PPP in aqueous solution was characterized by fluorescence probe technique, TEM, and DLS. The critical micelle concentration (CMC), thus, determined was 0.0187 g/L. Both TEM and DLS measurement suggested that the diameter of micelles was approximately 190 nm at 20 degrees C. Diflunisal (DIF)-loaded micelles were prepared by dialysis method. In vitro release test at various temperatures was also performed to study the effect of temperature on the drug release profiles. It was demonstrated that DIF release from PNIPAm-g-PPP micelles was slower at the temperature of 37 degrees C than that at 4 degrees C.

Thymosin-loaded enteric microspheres for oral administration: preparation and in vitro release studies.

Thymosin, a water-soluble polypeptide compound, was encapsulated within enteric microspheres of acrylic acid resin II by modified oil in oil (o/o) emulsion solvent evaporation method. The mixture emulsifier composed of lecithin and Span 80 was critical to the formation of sphere-shaped thymosin microparticles. Optimizing process parameters, such as the volume ratio of organic solvent to water, initial drug feed and polymer concentration, resulted in high drug encapsulation efficiency of 89.7% (6% polymer concentration and 0.5% initial drug feed). In vitro release studies suggested that thymosin release from microspheres exhibited pH dependent profiles. For formulation with 6% polymer concentration and 0.5% initial drug feed, 68.7% thymosin was released within 4h in pH 6.8 PBS buffer, while only 6.5% was observed in acid medium.

Physicochemical characterization of polymeric micelles constructed from novel amphiphilic polyphosphazene with poly(N-isopropylacrylamide) and ethyl 4-aminobenzoate as side groups.

An amphiphilic graft polyphosphazene (PNIPAm/EAB-PPP) composed of oligo-poly(N-isopropylacrylamide) (PNIPAm) as hydrophilic segments and ethyl 4-aminobenzoate (EAB) as hydrophobic groups was synthesized via ring-opening polymerization and subsequent substitution reaction. The molar ratio of the PNIPAm segment to EAB group was 1.85:0.15. The lower critical solution temperature (LCST) of copolymer was 32.6 degrees C as determined by turbidity method. Micellization behavior of PNIPAm/EAB-PPP in an aqueous phase was characterized by fluorescence technique, 1H NMR, dynamic light scattering (DLS) and transmission electron microscopy (TEM). The critical micelle concentration (CMC) of the graft copolymer in aqueous solution was 0.1mg/ml. The number-averaged particle size of spherical micelles was 80 nm at 25 degrees C with a narrow distribution. TEM also revealed that inter-micellar aggregation was induced in the micelle solution at temperature above LCST of graft copolymer. The thermosensitive PNIPAm/EAB-PPP micelles may be of help to regulate the loading and release of hydrophobic drugs.

[The study of the C5 nerve root palsy after surgery of cervical spondylosis].

OBJECTIVE: To explore the clinical features, treatment and prognosis of the C5 palsy after surgery of cervical spondylosis. METHODS: Two hundred and twenty-three cases treated from March 1994 to October 2003 were retrospectively reviewed. RESULTS: Seven of the 223 cases developed the complication of C5 palsy, manifesting the paresis of the deltoid muscle as well as the sensory deficits and (or) intractable pain in shoulder. The incidence was 3.1%. In this study, 2 cases occurred in the anterior subcorpectomy, 5 cases developed in the laminoplasty with 1 case on the opened side, 3 cases on the hinged side and 1 case on both sides. All the 7 cases with the C5 palsy recovered within 2 weeks to 6 months. CONCLUSION: The C5 palsy can develop either anterior decompression or posterior open-door laminoplasty of cervical spondylosis. Generally speaking, patients with postoperative C5 palsy can be cured by conservative measures. And prognosis is good.

Activation of Toll-like receptors by intestinal microflora reduces radiation-induced DNA damage in mice.

Activation of Toll-like receptors (TLRs) signaling by intestinal microflora-derived bacterial products plays a key role in injury defence for the host. We investigated the role of TLRs activated by intestinal microflora in radiation-induced DNA damage in mice. We analyzed DNA damage induced by 2Gy γ-ray radiation in an intestinal commensal bacteria-depleted mouse model (CD group), in which TLRs (TLR2/6, TLR4 and TLR5) ligand levels in serum were reduced. Chromosomal aberrations were measured in bone marrow cells and peripheral blood leukocyte comet assays were performed. DNA damage was increased in the CD group compared with the control group. Treatment of mice with TLR agonists (CBLB502, LPS and lipopeptide) 1h before radiation resulted in a significant decrease in DNA damage. Genes induced by TLR5 activation were analyzed; activation of TLRs regulated the expression of Gadd45b, Sod2, and Rad21, which are involved in DNA damage repair. In summary, our data indicate that TLRs activation by intestinal microflora reduces DNA damage induced by radiation and regulates expression of several DNA repair genes.

A de novo 1.38 Mb duplication of 1q31.1 in a boy with hemifacial microsomia, anophthalmia, anotia, macrostomia, and cleft lip and palate.

We reported a 2-year-old boy with developmental delay, mild mental retardation, and severe craniofacial malformation, including facial asymmetry with hypoplasia of the left zygoma, maxilla, and mandible, and left anophthalmia and anotia. A genome-wide screen revealed a 1.38 Mb duplication on chromosome 1q31.1, which was absent in his parents and 27 healthy controls. The duplication region contains two Refseq genes, PLA2G4A and C1orf99, which have not been reported to be implicated in craniofacial malformation. Functional studies of these genes and additional clinical analysis are necessary to elucidate the pathogenesis of craniofacial malformation.

Activation of the central histaminergic system is involved in hypoxia-induced stroke tolerance in adult mice.

We hypothesized that activation of the central histaminergic system is required for neuroprotection induced by hypoxic preconditioning. Wild-type (WT) and histidine decarboxylase knockout (HDC-KO) mice were preconditioned by 3 hours of hypoxia (8% O(2)) and, 48 hours later, subjected to 30 minutes of middle cerebral artery (MCA) occlusion, followed by 24 hours of reperfusion. Hypoxic preconditioning improved neurologic function and decreased infarct volume in WT or HDC-KO mice treated with histamine, but not in HDC-KO or WT mice treated with α-fluoromethylhistidine (α-FMH, an inhibitor of HDC). Laser-Doppler flowmetry analysis showed that hypoxic preconditioning ameliorated cerebral blood flow (CBF) in the periphery of the MCA territory during ischemia in WT mice but not in HDC-KO mice. Histamine decreased in the cortex of WT mice after 2, 3, and 4 hours of hypoxia, and HDC activity increased after 3 hours of hypoxia. Vascular endothelial growth factor (VEGF) mRNA and protein expressions showed a greater increase after hypoxia than those in HDC-KO or α-FMH-treated WT mice. In addition, the VEGF receptor-2 antagonist SU1498 prevented the protective effect of hypoxic preconditioning in infarct volume and reversed increased peripheral CBF in WT mice. Therefore, endogenous histamine is an essential mediator of hypoxic preconditioning. It may function by enhancing hypoxia-induced VEGF expression.