A Mussel-Inspired Conductive, Self-Adhesive, and Self-Healable Tough Hydrogel as Cell Stimulators and Implantable Bioelectronics.

A graphene oxide conductive hydrogel is reported that simultaneously possesses high toughness, self-healability, and self-adhesiveness. Inspired by the adhesion behaviors of mussels, our conductive hydrogel shows self-adhesiveness on various surfaces and soft tissues. The hydrogel can be used as self-adhesive bioelectronics, such as electrical stimulators to regulate cell activity and implantable electrodes for recording in vivo signals.

Osthole Promotes Endochondral Ossification and Accelerates Fracture Healing in Mice.

Osthole has been found to restore bone mass in preclinical osteoporotic models. In the present study, we investigated the effects of osthole on bone fracture repair in mice. Adult C57BL/6 mice were subjected to transverse femoral fractures and administrated orally with 20 mg/kg osthole and vehicle solvent daily from week 1 post-operation. Fracture callus were analyzed by plain radiography, micro-computed tomography, histology, molecular imaging and immunohistochemistry and tartrate-resistant acid phosphatase staining. Results demonstrated that osthole treatment enhanced removal of cartilage and bony union during reparative stage without significant interfering on remodeling process. In vivo molecular imaging showed bone formation rate of the treatment group was almost twofold of control group at week 2 post-operation. Osthole augmented the expression of alkaline phosphatase and collagen type X in hypertrophic chondrocytes as well as expression of bone morphogenetic protein-2, osteocalcin and alkaline phosphatase in osteoblastic cells, indicating it promoted mineralization of hypertrophic cartilage and woven bone growth simultaneously during endochondral healing. In summary, osthole promotes endochondral ossification via upregulation of maturation osteogenic marker genes in chondrocytes and subsequently accelerates fracture repair and bony fusion.

Perception of primary care doctors towards telemedicine in Kuching, Sarawak: A cross-sectional study.

Introduction: Telemedicine is the provision of healthcare remotely via information and communications technology (ICT). This study aimed to assess the familiarity and factors related to the perception towards telemedicine and the willingness to practise telemedicine among primary care doctors. Methods: A multi-centre cross-sectional study was conducted prospectively at all public healthcare clinics across Kuching, Sarawak. A questionnaire was adapted and modified from an overseas validated questionnaire, consisting of four parts: demographic data, familiarity towards telemedicine, factors related to the perception of telemedicine and willingness to implement telemedicine. Results: A total of 131 doctors were recruited. Of them, 43.5% had never interacted with patients via email, WhatsApp or Telegram, while 68.7% had never attended any conferences, speeches or meetings regarding telemedicine. The doctors had low familiarity towards guidelines, technology and medical applications of telemedicine. The majority agreed on the ability of telemedicine to save patients' time and money, the potential of ICT in healthcare and the necessity during a pandemic but perceived the possibility of technical difficulties. The doctors who had experience in interacting with patients via email, WhatsApp or Telegram (P=0.001) and those who had ≤8 years of working experience (P=0.04) had a significantly better perception towards telemedicine. Conclusion: Although the familiarity towards telemedicine among public primary care doctors is low, their perception is good in a majority of areas. Adequate technological support and continuous education on telemedicine and its guidelines, especially medicolegal issues, are imperative to adopt and propagate telemedicine in primary care.

Folate Deficiency Enhanced Inflammation and Exacerbated Renal Fibrosis in High-Fat High-Fructose Diet-Fed Mice.

The prevalence of obesity and chronic kidney disease (CKD) is increasing simultaneously and rapidly worldwide. Our previous study showed that folate deficiency increased lipid accumulation and leptin production of adipocytes. Whether folate plays a role in CKD, particularly obesity-related nephropathy remains unclear. To investigate the effects of folate deficiency on CKD in diet-induced obese mice, four groups of male C57BL/6 mice were fed either a normal-fat diet (NF) with folate (NF+f); NF without folate (NF-f); high-fat high-fructose diet (HFF) with folate (HFF+f); or HFF without folate (HFF-f) for 12 months during the study. The results showed that HFF increased not only body weight, fasting blood glucose, total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol, and blood pressure, but also cytokines levels, such as interleukin (IL)-2, interferon (IFN)-γ, IL-17A/F, IL-6, monocyte chemoattractant protein (MCP)-1, and transforming growth factor (TGF)-ß1. The indicators of kidney failure including urinary protein, neutrophil gelatinase-associated lipocalin (NGAL), renal type I and IV collagen deposits and leptin content, and serum creatinine were also increased by HFF. Folate-deficient diets further elevated serum TC, LDL-cholesterol, IL-6, tumor necrosis factor (TNF)-α, MCP-1, TGF-ß1, and leptin, but decreased IL-10 level, and thus exacerbated renal fibrosis. To investigate the possible mechanisms of folate deficiency on renal injury, phosphorylation of pro-fibrosis signaling molecules, including signal transducer and activator of transcription (STAT)3 and small mothers against decapentaplegic (Smad)2/3, were assayed. Both HFF and folate deficiency significantly increased the phosphorylation of STAT3 and Smad2/3, suggesting synergistic effects of HFF-f on chronic renal inflammation and fibrosis. In conclusion, the results demonstrated that folate deficiency might aggravate inflammatory status and enhance renal fibrosis.

Inter-observer and intra-observer reliability between manual segmentation and semi-automated segmentation for carotid vessel wall volume measurements on three-dimensional ultrasonography.

PURPOSE: Carotid vessel wall volume (VWV) measurement on three-dimensional ultrasonography (3DUS) outperforms conventional two-dimensional ultrasonography for carotid atherosclerosis evaluation. Although time-saving semi-automated algorithms have been introduced, their clinical availability remains limited due to a lack of validation, particularly an extensive reliability analysis. This study compared inter-observer and intra-observer reliability between manual segmentation and semi-automated segmentation for carotid VWV measurements on 3DUS. METHODS: Thirty-one 3DUS volume datasets were prospectively acquired from 20 healthy subjects, aged >18 years, without previous stroke, transient ischemic attack, or cardiovascular disease. Five observers segmented all volume datasets both manually and semi-automatically. The process was repeated five times. Reliability was expressed by the intraclass correlation coefficient, supplemented by the coefficient of variation. RESULTS: Carotid VWV measurements using the common carotid artery (CCA) were more reliable than those using the internal carotid artery (ICA) or external carotid artery (ECA) for both manual and semiautomated segmentation (manual segmentation, CCA: inter-observer, 0.935; intra-observer, 0.934 to 0.966; ICA: inter-observer, 0.784; intra-observer, 0.756 to 0.878; ECA: inter-observer, 0.732; intraobserver, 0.919 to 0.962; semi-automated segmentation, CCA: inter-observer, 0.986; intra-observer, 0.954 to 0.993; ICA: inter-observer, 0.977; intra-observer, 0.958 to 0.978; ECA: inter-observer, 0.966; intra-observer, 0.884 to 0.937). Total carotid VWV measurements by manual (inter-observer, 0.922; intra-observer, 0.927 to 0.961) and semi-automated segmentation (inter-observer, 0.987; intra-observer, 0.968 to 0.989) were highly reliable. Semi-automated segmentation showed higher reliability than manual segmentation for both individual and total carotid VWV measurements. CONCLUSION: 3DUS carotid VWV measurements of the CCA are more reliable than measurements of the ICA and ECA. Total carotid VWV measurements are highly reliable. Semi-automated segmentation has higher reliability than manual segmentation.

Temporal Machine Learning Analysis of Prior Mammograms for Breast Cancer Risk Prediction.

The identification of women at risk for sporadic breast cancer remains a clinical challenge. We hypothesize that the temporal analysis of annual screening mammograms, using a long short-term memory (LSTM) network, could accurately identify women at risk of future breast cancer. Women with an imaging abnormality, which had been biopsy-confirmed to be cancer or benign, who also had antecedent imaging available were included in this case-control study. Sequences of antecedent mammograms were retrospectively collected under HIPAA-approved guidelines. Radiomic and deep-learning-based features were extracted on regions of interest placed posterior to the nipple in antecedent images. These features were input to LSTM recurrent networks to classify whether the future lesion would be malignant or benign. Classification performance was assessed using all available antecedent time-points and using a single antecedent time-point in the task of lesion classification. Classifiers incorporating multiple time-points with LSTM, based either on deep-learning-extracted features or on radiomic features, tended to perform statistically better than chance, whereas those using only a single time-point failed to show improved performance compared to chance, as judged by area under the receiver operating characteristic curves (AUC: 0.63 ± 0.05, 0.65 ± 0.05, 0.52 ± 0.06 and 0.54 ± 0.06, respectively). Lastly, similar classification performance was observed when using features extracted from the affected versus the contralateral breast in predicting future unilateral malignancy (AUC: 0.63 ± 0.05 vs. 0.59 ± 0.06 for deep-learning-extracted features; 0.65 ± 0.05 vs. 0.62 ± 0.06 for radiomic features). The results of this study suggest that the incorporation of temporal information into radiomic analyses may improve the overall classification performance through LSTM, as demonstrated by the improved discrimination of future lesions as malignant or benign. Further, our data suggest that a potential field effect, changes in the breast extending beyond the lesion itself, is present in both the affected and contralateral breasts in antecedent imaging, and, thus, the evaluation of either breast might inform on the future risk of breast cancer.

Folate Deficiency Increased Lipid Accumulation and Leptin Production of Adipocytes.

Imbalanced dietary habits are closely associated with poor micronutrients status and the development of obesity. Previous studies have shown that serum folate level is decreased in obese individuals. However, whether folate deficiency could result in adiposity is still unclear. The aim of this study was to investigate the effects of dietary folate on lipid accumulation and leptin production using both in vivo and in vitro studies. Male C57BL/6 mice were fed with a diet with (f1) or without (f0) folate in a high-fat (HF) diet containing high-sucrose (HFS-f1, HFS-f0) for 4.5-5 months in Experiment 1, or an HF diet (HF-f1, HF-f0) for 12 months in Experiment 2, or an HF diet containing high-fructose (HFF-f1, HFF-f0) for 12 months in Experiment 3, compared with the normal-fat (NF-f1, NF-f0) diet, respectively. The serum levels of folate and leptin, white adipose tissue (WAT), size of adipocytes, hepatic contents of triglyceride (TG), and cholesterol were measured. In vitro study, TG contents, proinflammatory cytokines, leptin, and expressions of hypoxia-inducible factor (HIF)-1α and lipogenesis-related genes of 3T3-L1 adipocytes cultured with (f1) or without (f0) folate were assayed. The results showed that folate deficiency together with a high-fat diet (HFS-f0, HF-f0, HFF-f0) had higher WAT mass, adipocyte size, serum leptin level, and hepatic TG compared to those of the folate-sufficient groups (HFS-f1, HF-f1, and HFF-f1). Folate deficiency with a high-fat high -sucrose or -fructose diet (HFS-f0, HFF-f0) significantly increased the body weight of the mice. Increased intracellular TG, leptin, monocyte chemotactic protein (MCP)-1 and interleukin (IL)-6 levels, and the expression of Hif1α and lipogenesis-related genes Cebpα, Cebpß, Acc1, Fasn, and Fabp4 were also detected in folate-deficient 3T3-L1 adipocytes. Our results suggested that folate deficiency increased lipid accumulation and leptin production of adipocytes, and thus, inadequate folate status might be one of the risk factors for adiposity.

Medication Adherence of Persons with Type 2 Diabetes in Malaysia: A Scoping Review and Meta-Analysis.

Objective: This is a scoping review of Malaysian scientific studies on medication adherence among persons with type 2 diabetes mellitus (T2DM). Methodology: We conducted a bibliographic search of PubMed, Scopus and Google Scholar using the following keywords: "medication adherence," "drug compliance," "DMTAC" and "Malaysia." The search covered all publications up to 31 December 2021. Eligible articles were original studies conducted in Malaysia that measured or quantified medication adherence among persons with T2DM. Results: We identified 64 eligible studies published between 2008 to 2021. Most studies included patients with T2DM in ambulatory facilities. Five studies were qualitative research. The quantitative research publications included clinical trials, and cross-sectional, validation, retrospective and prospective cohort studies. Thirty-eight studies used medication adherence scales. The Morisky Medication Adherence Scale (MMAS-8, used in 20 studies) and Malaysian Medication Adherence Scale (MALMAS, used in 6 studies) were the most commonly used tools. There were 6 validation studies with 4 medication adherence scales. A meta-analysis of 10 studies using MMAS-8 or MALMAS revealed that the pooled prevalence of low medication adherence is 34.2% (95% CI: 27.4 to 41.2, random effects model). Eighteen publications evaluated various aspects of the Diabetes Medication Therapy Adherence Clinics (DMTAC). Conclusion: This scoping review documented extensive research on medication adherence among persons with diabetes in Malaysia. The quantitative meta-analysis showed a pooled low medication adherence rate.

Pitfalls in interpreting rat knee joint magnetic resonance images and their histological correlation.

BACKGROUND: Magnetic resonance (MR) imaging has been increasingly used as an investigational tool for assessing the structure and function of animal joint disease models, while to date MR tomographic knowledge of laboratory animal skeletal microanatomy remains limited. PURPOSE: To describe pitfalls in interpreting rat knee joint MR images and their histological correlation. MATERIAL AND METHODS: MR scans of the right knee of five 3-month-old Sprague-Dawley (SD) rats were carried out using a 4.7T magnet, using a fat-suppressed three-dimensional (3D) gradient echo sequence with a spatial resolution of 59 x 117 x 234 microm. Histology assessment with hematoxylin and eosin staining and Safranin O staining was carried out in the five 3-month-old SD rats and two SD rats of 1 month and 6 months old, respectively. MR images were analyzed by a radiologist, and histology data were assessed by a radiologist and a pathologist. RESULTS: Though the MR images were acquired in normal rats, many signs unfamiliar to radiologists were noted, including notch-like bright signal areas in the epiphysis, gray signal areas in the epiphysis, and fuzzy joint surface of the epiphysis of the femur and tibia. Detailed inspection of the histology specimen showed more unfamiliar features of rat knee microanatomy, including curvy or dipped surface of the femur/tibia epiphysis, areas composed of a mixture of cartilage and bone components, normal notch structure, cyst-like structure, and cavity between cortical lamellae under the joint cartilage. CONCLUSION: There are a number of normal microstructures of the rat knee joint that can be potentially misinterpreted as arthritic changes on MR images. Recognizing these rat knee microstructures can help correct image reading during biomedical research.

Low-dose X-irradiation promotes mineralization of fracture callus in a rat model.

OBJECTIVES: This study investigated the hypothesized beneficial effect of low-dose irradiation (LDI) on fracture callus mineralization in a rat model. METHODS: Seventy-two male Sprague-Dawley rats were averagely randomized into LDI group (rats treated with LDI) and SHAM group (rats treated with sham irradiation). Right after either LDI or sham irradiation, a standardized closed fracture on the right femur was established. At 2, 3 and 4 weeks postfracture, 12 rats in each group were euthanized. Fracture callus was assessed by using radiography and MicroCT for callus bridging, peripheral quantitative computed tomography (pQCT) for quantifying bone mineral content (BMC) and cross sectional area (CSA), confocal laser scanning microscopy for measuring area fraction of fluorescence labeling (AFFL) and four-point bending test for examining mechanical properties. RESULTS: The CSA and AFFL were found to be 22 and 33% smaller in the LDI group compared to the SHAM group at 2 weeks (P<0.05 for both), whereas the BMC and AFFL were 15 and 34% higher in the LDI group at 3 weeks (P<0.05 for both). The changing patterns were consistent with the findings in 3-D MicroCT reconstructions. The mechanical parameters (Max-Load, Stiffness and Energy) were also 18, 30 and 24% higher in the LDI group than in the SHAM group at 3 weeks (P<0.05 for all). At 4 weeks, there was no difference found for all assessments between the two groups. CONCLUSION: The results indicated LDI promoted mineralization at the stage of hard callus formation in a rat fracture model.

Biodegradable Thermosensitive PLGA-PEG-PLGA Polymer for Non-irritating and Sustained Ophthalmic Drug Delivery.

Challenges of ophthalmic drug delivery arise from not only the limited solubility of hydrophobic therapeutics, but also the restricted permeability and fast clearance of drugs due to the complex anatomy and physiology of the eyes. Biodegradable thermosensitive polymer, poly(dl-lactide-co-glycolide-b-ethylene glycol-b-dl-lactide-co-glycolide) (PLGA-PEG-PLGA) is a desirable ophthalmic drug delivery system because it can be formulated into injectable solution which forms gel in situ to provide prolonged drug release. In this study, excellent biocompatibility of blank PLGA-PEG-PLGA (1800-1500-1800) thermogel was demonstrated with insignificant difference from saline noted in rat eye enucleation test, in vivo inflammation test upon topical instillation, and subconjunctival injection. After subconjunctival injection, thermogel formulations loaded with hydrophilic (rhodamine B) or hydrophobic (coumarin 6) fluorescent dyes were retained up to 4 weeks in eye tissues and significantly higher level was detected than rhodamine B solution or coumarin 6 suspension in weeks 3 and 4. Moreover, in vivo whole body imaging showed that dye-loaded (sulfo-cyanine 7 NHS ester, Cy7; or cyanine 7.5 alkyne, Cy7.5) thermogels had longer retention at the injection site and retarded release to other body parts than dye solutions. Generally, the release rate of hydrophobic dyes (coumarin 6 and Cy7.5) was much slower than that of the hydrophilic dyes (rhodamine B and Cy7) from the thermogel. In summary, the thermogel was safe for ophthalmic drug delivery and could deliver both hydrophobic and hydrophilic compounds for sustained drug release into eye tissues with single subconjunctival injection for better patient compliance and reduced risks on repeated injection.

Mussel-inspired dopamine oligomer intercalated tough and resilient gelatin methacryloyl (GelMA) hydrogels for cartilage regeneration.

Gelatin methacryloyl (GelMA) hydrogels are widely used for tissue regeneration. Nonetheless, a pure GelMA hydrogel cannot efficiently serve for cartilage regeneration because of weak mechanical properties and brittleness. In this study, we established a mussel-inspired strategy for tuning the mechanical properties of GelMA hydrogels by intercalating oligomers of dopamine methacrylate (ODMA) into the chain of GelMA. After the ODMA intercalated, the hydrogel became tough and resilient. This is because ODMA intercalation reduces the high density of entangled GelMA chains and introduces additional sacrificial physical cross-linking into the hydrogel. Rheological analysis showed that the ODMA-GelMA hydrogel was mechanically stable at body temperature. The hydrogel also manifested a sustained protein release because of the ODMA catechol groups. Furthermore, the ODMA-GelMA hydrogel was found to have good biocompatibility and affinity for cells and tissues because of the catechol groups on ODMA. In vitro, the hydrogel promoted mesenchymal stem cell adhesion and growth, and in vivo, it promoted cartilage regeneration after loading with chondroitin sulfate or TGF-ß3. The hydrogel can serve as a growth-factor-free scaffold for cartilage regeneration. This hydrogel not only provided a favorable microenvironment for cartilage repair but also could serve as a promising candidate material for repair of other tissues. This mussel-inspired strategy of introduction of reactive oligomers instead of polymers into a brittle hydrogel network may be extended to the development of other tough hydrogels for biomedical applications.

Acupuncture and herbal moxibustion for the treatment of 'BiQiu' (allergic rhinitis symptoms) in a Hong Kong Chinese medicine clinic: a randomized controlled trial.

BACKGROUND: Allergic rhinitis (AR) is a common disease. No evidence is available for the clinical application of acupuncture and moxibustion for the management of AR symptoms in Hong Kong. This study aimed to evaluate the clinical effectiveness of acupuncture with or without herbal moxibustion on relieving AR symptoms in the Hong Kong population. METHODS: A single-centre, randomized, assessor-blinded, controlled trial with three parallel arms (acupuncture alone, acupuncture combined with herbal moxibustion treatment and waitlist) was designed. Groups with acupuncture treatment received treatment 3 times per week for a total of 12 sessions in 4 weeks. Acupuncture combined with herbal moxibustion treatment group received herbal moxibustion once per week for a total of 4 sessions over 4 weeks in addition to acupuncture treatment. Participants in the waitlist group received no treatment. All patients received advice on healthy lifestyle, diet, and exercise. RESULTS: Ninety-six subjects were recruited and allocated randomly (1:1:1) into three study groups. Compared to the waitlist group, both treatment groups demonstrated statistically significant decreases in TNSS and RQLQ at the end of treatment as well as after follow-up period (all P < 0.01). However, there was no statistically differences between these two treatment groups. There was no difference in the change of total IgE levels among study groups before or after the treatment. Only one patient reported adverse effects with herbal moxibustion treatment, and no adverse effects were found in others. CONCLUSIONS: This study supports that acupuncture could help relieve AR symptoms, but no evidence on additional treatment effect of herbal moxibustion was found.Trial registration ChiCTR-INR-16010047 registered on November 25, 2016.

Pharmacotherapeutic management of gout in patients with cardiac disease.

INTRODUCTION: Hyperuricemia has been identified as an independent risk factor for coronary artery disease (CAD). Uric acid lowering therapy could potentially lower the risk of CAD. Conventional treatments have been effective in treating acute gout flares in most patients, but certain options, like NSAIDs could increase the risk of CAD. AREAS COVERED: This review covers the aspect of cardiac safety with traditional and new medications used in treating both acute flares and chronic gout according to the most recent international guidelines. EXPERT OPINION: All NSAIDs, not just selective Cox 2 inhibitors, have associated with them different degrees of cardiac risk; therefore, NSAIDs should be avoided when treating patients with underlying CAD. Interleukin-1 inhibitors appear to be safe alternatives for treating cardiac patients who are contraindicated to conventional treatment. Presently, there is a paucity of evidence concerning whether treatment of hyperuricemia could lower the risk of CAD and this must be explored further. It is also important to explore the cardiac safety of plegloticase to better ascertain its safety in CAD patients.

Mussel-Inspired Tissue-Adhesive Hydrogel Based on the Polydopamine-Chondroitin Sulfate Complex for Growth-Factor-Free Cartilage Regeneration.

Glycosaminoglycan-based hydrogels are widely used for cartilage repair because glycosaminoglycans are the main component of the cartilage extracellular matrix and can maintain chondrocyte functions. However, most of the glycosaminoglycan-based hydrogels are negatively charged and cell-repellant, and they cannot host cells or favor tissue regeneration. Inspired by mussel chemistry, we designed a polydopamine-chondroitin sulfate-polyacrylamide (PDA-CS-PAM) hydrogel with tissue adhesiveness and super mechanical properties for growth-factor-free cartilage regeneration. Thanks to the abundant reactive catechol groups on the PDA, a cartilage-specific PDA-CS complex was formed by the self-assembly of PDA and CS, and then the PDA-CS complex was homogenously incorporated into an elastic hydrogel network. This catechol-group-enriched PDA-CS complex endowed the hydrogel with good cell affinity and tissue adhesiveness to facilitate cell adhesion and tissue integration. Compared with bare CS, the PDA-CS complex in the hydrogel was more effective in exerting its functions on adhered cells to upregulate chondrogenic differentiation. Because of the synergistic effects of noncovalent interactions caused by the PDA-CS complex and covalently cross-linked PAM network, the hydrogel exhibited super resilience and toughness, meeting the mechanical requirement of cartilage repair. Collectively, this tissue-adhesive and tough PDA-CS-PAM hydrogel with good cell affinity creates a growth-factor-free and biomimetic microenvironment for chondrocyte growth and cartilage regeneration and sheds light on the development of growth-factor-free biomaterials for cartilage repair.

Downregulation of glutamatergic and GABAergic proteins in valproric acid associated social impairment during adolescence in mice.

The etiology of Autism Spectrum Disorder (ASD) remains controversial. Deficits in social communication are one of the key criteria for ASD diagnosis. Valproic acid (VPA), which is an anti-epileptic and anti-depressive drug, is one of the teratogens to cause ASD onset. Moreover, synaptic dysfunction is suggested as one of the major causative factor in VPA-induced ASD in vitro and in vivo studies. Herein, this study aimed to determine the excitatory/inhibitory synaptic mRNA and protein expression in VPA-induced autistic mice. Pregnant BALB/c mice were injected peritoneally with a single dose of 600mg/kg VPA on embryonic day (E) 12.5. Social impairment was verified by three chamber sociability tests on postnatal days (PND) 28, 35, 42 and 49. Cortical synaptic mRNA and protein expressions were examined on PND 50. The excitatory synaptic proteins NR2A, NR2B, NR2C were significantly down-regulated by 80.0% (p<0.01), 51.5% (p<0.05) and 81.5% (p<0.05) respectively. Furthermore, the NMDAR expression regulatory protein BDNF was also found to be significantly downregulated by 76.8% (p<0.05). GAD65, GAD67, GABRA1, GABRA5, GABRB2 from the GABAergic inhibitory synaptic pathway were significantly downregulated by 21.3% (p<0.05), 77.0% (p<0.05), 53.9% (p<0.05), 56.9% (p<0.05) and 55.2% (p<0.01) respectively in the cortex of VPA-induced mice. Taken together, our results suggested that synaptic dysfunction might be involved in the social impairments in VPA-induced ASD.

Osthole Enhances Osteogenesis in Osteoblasts by Elevating Transcription Factor Osterix via cAMP/CREB Signaling In Vitro and In Vivo.

Anabolic anti-osteoporotic agents are desirable for treatment and prevention of osteoporosis and fragility fractures. Osthole is a coumarin derivative extracted from the medicinal herbs Cnidium monnieri (L.) Cusson and Angelica pubescens Maxim.f. Osthole has been reported with osteogenic and anti-osteoporotic properties, whereas the underlying mechanism of its benefit still remains unclear. The objective of the present study was to investigate the osteopromotive action of osthole on mouse osteoblastic MC3T3-E1 cells and on mouse femoral fracture repair, and to explore the interaction between osthole-induced osteopromotive effect and cyclic adenosine monophosphate (cAMP) elevating effect. Osthole treatment promoted osteogenesis in osteoblasts by enhancing alkaline phosphatase (ALP) activity and mineralization. Oral gavage of osthole enhanced fracture repair and increased bone strength. Mechanistic study showed osthole triggered the cAMP/CREB pathway through the elevation of the intracellular cAMP level and activation of the phosphorylation of the cAMP response element-binding protein (CREB). Blockage of cAMP/CREB downstream signals with protein kinase A (PKA) inhibitor KT5720 partially suppressed osthole-mediated osteogenesis by inhibiting the elevation of transcription factor, osterix. In conclusion, osthole shows osteopromotive effect on osteoblasts in vitro and in vivo. Osthole-mediated osteogenesis is related to activation of the cAMP/CREB signaling pathway and downstream osterix expression.

Low intensity pulsed ultrasound accelerated bone remodeling during consolidation stage of distraction osteogenesis.

Bone regeneration in distraction osteogenesis occurs under tensile stress with axial rhythmic distraction after osteotomy. In this study, we evaluated if the low intensity pulsed ultrasound (LIPUS) was also effective on enhancement of bone remodeling during consolidation stage of distraction osteogenesis. Open osteotomy of seventeen 18-week-old female New Zealand rabbit tibiae were performed. The distraction was applied with the rate of 1 mm per day. LIPUS (30 mW/cm(2), 1.5 MHz) was delivered for 20 min per day during 4-week consolidation stage (n=10). The animals without treatment served as sham group (n=7). Plain X-ray, peripheral quantitative computational tomography (pQCT), and torsional test were performed. Results showed that smaller radiolucent interzone of LIPUS treatment group was gradually occupied by calcified tissue in plain X-ray at week 2. The bone mineral density (BMD) measured on radiographs increased by 9.18% in the LIPUS group. Bone mineral content (BMC), hard callus volume, and bone strength index (BSI) measured by pQCT were 83%, 116%, and 94%, respectively, in LIPUS group that were significantly greater than those of the controls. At the 4th week, LIPUS-treated callus showed the development of neocorticalization in the proximal and distal region. The BMC, hard callus volume, and BSI of LIPUS group decreased and was not significantly different from control. This was also confirmed by the maximum torque of LIPUS-treated callus (1424.2+/-457.3 N . mm) obtained at week 4, which did not differ from that of the sham group (1968.8+/-895.1 N . mm). In conclusion, the effective period of LIPUS treatment was at the initial stage of consolidation, with accelerated bone formation and remodeling.

Dose-dependent effect of low-intensity pulsed ultrasound on callus formation during rapid distraction osteogenesis.

Distraction osteogenesis of bone or callotasis causes poor bone formation when the distraction rate is beyond the optimal rate. Low-intensity pulsed ultrasound was reported to enhance fracture healing, treatment of nonunion, and accelerate bone maturation and remodeling during consolidation stage of distraction osteogenesis. In this study, we evaluated the efficacy of different durations of LIPUS treatments during rapid bone lengthening. After 7-day latent period, osteotomized New Zealand white rabbit tibiae were lengthened at the rate of 2 mm per day for 1 week. Two different LIPUS treatment durations of 20 min and 40 min were selected for treatment groups. Rabbits without treatment served as the control group. Plain X-ray, peripheral quantitative computed tomography (pQCT) and histology were performed to assess bone acquisition in the distraction callus. The results showed that LIPUS increased bone mineral content and volume of the mineralized tissue of distraction callus in a dose-dependent manner. The different regions of distraction callus exhibited various spatial response to LIPUS treatment. Moreover, LIPUS enhanced dose-dependant endochondral formation. Compared with 20-min treatment, the 40-min LIPUS treatment was a more favorable treatment duration for bone regeneration in the distraction callus. In conclusion, LIPUS was able to enhance bone regeneration under rapid distraction, and its effect was dose-dependent.