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This study investigated the immediate biomechanical effects of a biter-width partial medial meniscectomy. Small tears on the free edge of the meniscus are occasionally discovered during arthroscopic knee procedures. Removal of these tears often requires no more width than that of a biter from the edge. While past cadaveric partial meniscectomy studies have reported on the effects of meniscectomies from resection of one-third to three-quarters of meniscal width, the biomechanical sequelae of substantially smaller meniscectomies remain unknown. This study was performed to determine how single-biter-width meniscectomies affect the pressure distribution and peak pressure on the tibial plateau, as these parameters are correlated with increased likelihood of development of osteoarthritis. Eight cadaveric knees were instrumented with a thin-film pressure sensor underneath the menisci while retaining the major ligaments and most of the capsule. Knees were loaded to 1000 N at angles of flexion of 0, 15, 30, and 45 in normal tibio-femoral angles and in 7° of varus. Pressure, peak pressure, force and contact area were recorded. Afterwards, biter-width meniscectomies were performed, and measures repeated. There were significant changes in contact area at most flexion and tibio-femoral angles. There were no changes in the amount of force that was transmitted through the medial compartment. The overall pressure on the tibial plateau did not change in most knee conditions and peak pressure did not change significantly in any condition. The changes in contact area were consistent with our expectations. Similarly, the lack of change in force was also expected. However, the lack of significant changes in pressure and peak pressure represent findings indicating that a biter sized meniscectomy may have clinically insignificant effects on biomechanics.

Currently, antibiotics are commonly used to treat coccidiosis, a severe protozoal disease in chickens. However, due to growing concerns about the antibiotic residue in meat and eggs, phytogenic formulations are becoming an attractive approach to manage this disease. In this study, we investigated the anti-coccidial function and mechanism of phytogenic formulations composed of Bidens pilosa, Artemisia indica, and both used in combination. We found that these formulations increased the survival rate and reduced body weight loss, the feed conversion ratio, oocyst excretion, bloody stools, and gut lesions of chickens. Mechanistic studies showed that A. indica, but not B. pilosa, reduced the survival of Eimeria oocysts. Accordingly, they both inhibited oocyst sporulation and sporozoite invasion into Madin-Darby bovine kidney (MDBK) cells. Overall, we demonstrate that these formulations protect chickens against coccidiosis. Moreover, a combination of B. pilosa and A. indica has an additive effect on coccidiosis control and growth performance in chickens compared to either one used alone.

Summary Background Diabetes prevalence is increasing in most places in the world, but prevalence is affected by both risk of developing diabetes and survival of those with diabetes. Diabetes incidence is a better metric to understand the trends in population risk of diabetes. Using a multicountry analysis, we aimed to ascertain whether the incidence of clinically diagnosed diabetes has changed over time. Methods In this multicountry data analysis, we assembled aggregated data describing trends in diagnosed total or type 2 diabetes incidence from 24 population-based data sources in 21 countries or jurisdictions. Data were from administrative sources, health insurance records, registries, and a health survey. We modelled incidence rates with Poisson regression, using age and calendar time (1995–2018) as variables, describing the effects with restricted cubic splines with six knots for age and calendar time. Findings Our data included about 22 million diabetes diagnoses from 5 billion person-years of follow-up. Data were from 19 high-income and two middle-income countries or jurisdictions. 23 data sources had data from 2010 onwards, among which 19 had a downward or stable trend, with an annual estimated change in incidence ranging from −1·1% to −10·8%. Among the four data sources with an increasing trend from 2010 onwards, the annual estimated change ranged from 0·9% to 5·6%. The findings were robust to sensitivity analyses excluding data sources in which the data quality was lower and were consistent in analyses stratified by different diabetes definitions. Interpretation The incidence of diagnosed diabetes is stabilising or declining in many high-income countries. The reasons for the declines in the incidence of diagnosed diabetes warrant further investigation with appropriate data sources. Funding US Centers for Disease Control and Prevention, Diabetes Australia Research Program, and Victoria State Government Operational Infrastructure Support Program.

DNA methylation is an important epigenetic regulator in gene expression and has several roles in cancer and disease progression. MethHC version 2.0 (MethHC 2.0) is an integrated and web-based resource focusing on the aberrant methylomes of human diseases, specifically cancer. This paper presents an updated implementation of MethHC 2.0 by incorporating additional DNA methylomes and transcriptomes from several public repositories, including 33 human cancers, over 50 118 microarray and RNA sequencing data from TCGA and GEO, and accumulating up to 3586 manually curated data from >7000 collected published literature with experimental evidence. MethHC 2.0 has also been equipped with enhanced data annotation functionality and a user-friendly web interface for data presentation, search, and visualization. Provided features include clinical-pathological data, mutation and copy number variation, multiplicity of information (gene regions, enhancer regions, and CGI regions), and circulating tumor DNA methylation profiles, available for research such as biomarker panel design, cancer comparison, diagnosis, prognosis, therapy study and identifying potential epigenetic biomarkers. MethHC 2.0 is now available at http://awi.cuhk.edu.cn/∼MethHC.

To evaluate the diagnostic value of serum Brain-derived neurotrophic factor (BDNF) levels for discriminating PD with depression from without depression, and to investigate whether serum BDNF levels were associated with motor severity and gender in depressed PD patients. Demographic and clinical data were collected from 122 PD patients with depression, 137 without depression and 110 healthy controls. All participants’ serum BDNF concentrations were measured. Their motor abilities and activity were assessed by the Unified PD Rating Scale Part III (UPDRS III) score and the Hoehn and Yahr (H–Y) stage. Depression was scored using the 17-item Hamilton Rating Scale for Depression (HAMD-17). Associations were analyzed with multivariate regression. The serum BDNF levels were lower in depressed PD patients compared to non-depressed PD patients and controls (p

This study investigated the effects of low-intensity pulsed ultrasound (LIPUS) of different spatial-average-temporal-average intensity (ISATA) ranging from 15–150 mW/cm2 on the treatment of osteoporosis in ovariectomized rats. Healthy 3-mo-old female Sprague–Dawley rats were randomly divided into nine groups (n = 12 per group): sham-ovariectomy (OVX) control group, OVX control group and OVX groups treated with LIPUS at seven different intensities (ISATA: 15, 30, 50, 75, 100, 125 and 150 mW/cm2, respectively). LIPUS was applied to bilateral femurs 12 wk post-OVX for 20 min/d for 6 wk. Micro-computed tomography, biomechanical tests, serum biochemical analysis and grip strength tests were performed to evaluate the therapeutic effects of LIPUS at different intensities. Results revealed that LIPUS intensity yielded strong correlations with bone mineral density and bone microstructure (R2 = 0.57–0.83) and bone mechanical strength (R2 = 0.80–0.97), and that the intensity of 150 mW/cm2, instead of the 30 mW/cm2 widely used in bone fracture healing, was most effective in maintaining bone mass among all the LIPUS signals between 15 and 150 mW/cm2. This suggests that higher ultrasound intensity (i.e., 150 mW/cm2) may be more effective than lower intensity in mitigation of osteopenia and osteoporosis.

Objective: To objective of the study was to investigate whether serum brain-derived neurotrophic factor (BDNF) levels are associated with the severity of restless legs syndrome (RLS) in Parkinson's disease (PD).Methods: A total of 249 PD patients with (n = 53) and without RLS (n = 196) and 326 age-matched controls were included in this study. All the serum BDNF levels of the participants were measured. The International Restless Legs Syndrome Study Group Rating Scale (IRLSSG-RS) was administered for the severity of RLS. The severity of PD patients were assessed by the Unified PD Rating Scale (UPDRS) and the Hoehn and Yahr (H-Y) stage.Results: The prevalence of RLS was significantly higher in PD patients (21.3%) than in the controls group (7.4%) (p < 0.05). The IRLSSG-RS score in PD patients with RLS (16.25 ± 5.24) was significantly increased than in controls with RLS (12.08 ± 3.99) (p < 0.01). The serum BDNF levels were significantly decreased in PD patients with RLS than in PD patients without RLS, controls without RLS, and controls with RLS (p < 0.001). BDNF levels were negatively associated with IRLSSG-RS in both PD patients with RLS and controls with RLS group (both p < 0.01). Multiple regression analysis confirmed that in either PD with RLS or controls with RLS group, BDNF was an independent contributor to IRLSSG-RS (both p < 0.01).Conclusions: Decreased serum BDNF levels may be involved in the pathophysiology of RLS in PD, suggesting that it may serve as a potential blood biomarker of diagnostic value for RLS in PD.

Orientin is a flavonoid monomer. In recent years, its importance as a source of pharmacological active substance is growing rapidly due to its properties such as anti-myocardial ischemia, anti-apoptosis, anti-radiation, anti-tumor, and anti-aging. However, the neuroprotective effects of Orientin on stroke injury have not been comprehensively evaluated. The aim of the present study was thus to investigate the neuroprotective capacity and the potential mechanisms of Cyperus esculentus L. orientin (CLO) from Cyperus esculentus L. leaves against ischemia/reperfusion (I/R) injury using standard orientin as control. For in vitro studies, we treated HT22 cells with CoCl2 as an in vitro ischemic injury model. HT22 cells in the control group were treated with CoCl2. For in vivo studies, we used rat models of middle cerebral artery occlusion, and animals that received sham surgery were used as controls. We found that CLO protected CoCl2-induced HT22 cells against ischemia/reperfusion injury by lowering lipid peroxidation and reactive oxygen species formation as well as decreasing protein oxidation. However, CLO did not reduce the release of lactate dehydrogenase nor increase the activity of superoxide dismutase. Results showed that CLO could decrease neurological deficit score, attenuate brain water content, and reduce cerebral infarct volume, leading to neuroprotection during cerebral ischemia-reperfusion injury. Our studies indicate that CLO flavonoids can be taken as a natural antioxidant and bacteriostastic substance in food and pharmaceutical industry. The molecular mechanisms of CLO could be at least partially attributed to the antioxidant properties and subsequently inhibiting activation of casepase-3. All experimental procedures and protocols were approved on May 16, 2016 by the Experimental Animal Ethics Committee of Xinjiang Medical University of China (approval No. IACUC20160516-57).

It has been demonstrated that articular facet degeneration can cause local strain alterations and induce neck pain. This study aims to quantify the biomechanical effects of normal and degenerated C5-C6 articular facets, and evaluate the correlation of mechanical strain between healthy and degenerated spine. A 3-dimensional finite element (FE) model of the C5-C6 cervical spine was developed [Model 0 (M0)]. The asymmetric models of C5-C6 bilateral articular facet joint were established separately to mimic articular facet joint degeneration. The capsule ligament stiffness of C5-C6 unilateral facet joint was altered with minimum and maximum threshold to simulate capsule ligaments' lesion and calcification [Model 1 (M1) and Model 2 (M2), respectively]. Besides, the cervical C5-C6 unilateral articular facet joint direction was changed by 5° and 10° forward to imitate the moderate joint hyperplasia and severe osteophyte (Model 3 and Model 4 respectively). M1 increased the rotation range of ipsilateral side (left), while M2 reduced, and both had limited effect on the contralateral side (right). The angle increased in Model 3 (M3) (61°) and Model 4 (M4) (55°) comparing to M0 during the axial rotation, and the angle of M4 was larger. M3 and M4 increased the nucleus pulposus pressure with and without controlled angular displacement during axial rotation. The pressure of nucleus pulpous increased during M1 rotating to the abnormal side but decreased when rotating to the other side, but the results of M2 were opposite. The capsule ligament stiffness made an impact on segmental mobility and vertebral spatial position, and the sagittal angle of articular facet joint exerted an influence on disc pressure distribution.

The purpose of this study was to evaluate the effect of low-intensity ultrasound on articular cartilage and subchondral bone alterations in joints under normal and functional disuse conditions during osteoarthritis (OA) progression. Total of thirty 5-mo-old female Sprague–Dawley rats were randomly assigned to six groups (n = 5/group): age-matched group, OA group, OA + ultrasound (US) group, hindlimb suspension (HLS) group, HLS + OA group and HLS + OA + US group. The surgical anterior cruciate ligament was used to induce OA in the right knee joints. After 2 wk of OA induction, low-intensity ultrasound generated with a 3-MHz transducer with 20% pulse duty cycle and 30 mW/cm2 acoustic intensity was delivered to the right knee joints for 20 min a day, 5 d a week for a total of 6 wk. Then, the right tibias were harvested for micro-computed tomography, histologic and mechanical analysis. Micro-computed tomography results indicated that the thickness and sulfated glycosaminoglycan content of cartilage decreased, but the thickness of the subchondral cortical bone plate and the formation of subchondral trabecular bone increased in the OA group under the normal joint use condition. Furthermore, histologic results revealed that chondrocyte density and arrangement in cartilage corrupted and the underlying subchondral bone increased during OA progression. These changes were accompanied by reductions in mechanical parameters in OA cartilage. However, fewer OA symptoms were observed in the HLS + OA group under the joint disuse condition. The cartilage degeneration and subchondral bone sclerosis were alleviated in the US treatment group, especially under normal joint use condition. In conclusion, low-intensity ultrasound could improve cartilage degeneration and subchondral sclerosis during OA progression. Also, it could provide a promising strategy for future clinical treatment for OA patients.

Objective It remains unclear whether transcranial magnetic stimulation (TMS) can replace the Wada test to determine language hemisphere dominance (HD). Using the Wada test as the gold standard, this study aimed to investigate the accuracy of navigated TMS (nTMS) in determining language HD. Methods This study enrolled nine right-handed patients with drug-resistant epilepsy. We hypothesized that application of nTMS to language-related areas of the language-dominant hemisphere would induce positive manifestation of language dysfunction (LD). To test our hypothesis, the patients were instructed to perform a visual object-naming task while nTMS was applied to the anterior (e.g., Broca’s area) and posterior (e.g., Wernicke’s area) regions, which are closely related to language processing. The Wada test result was used as the gold standard, and the diagnostic value of nTMS was assessed using the Kappa consistency test. Results The nTMS-induced LD positive rate for the bilateral anterior language areas (85.7%) was higher than that for the posterior language areas (57.1%). There was high consistency between nTMS stimulation of the left anterior and posterior language areas and the Wada test results for determining language HD. In contrast, the consistency of stimulation of the right anterior and posterior transfer sites was moderate (Kappa value = 0.545, P = 0.171) and low, respectively. For the latter, no statistical calculation was performed because stimulation of the right posterior speech area was negative in all patients compared with the Wada test results. Conclusions Our findings revealed that using nTMS to stimulate language-related left anterior and posterior areas could predict language HD with high accuracy. When the stimulation performance of these areas is positive, nTMS and the Wada test are equally accurate. Observing only negative performance may indicate that language HD has been transferred to the right side.

Background: Hepatocellular carcinoma with right atrial tumor thrombus is uncommon but with a dismal prognosis. Methods: By comprehensive retrieval of literature published between 2000 and 2019, 53 reports were obtained with 187 patients recruited into this study. The extracted data included patient characteristics, tumor characteristics, treatment, follow-up and outcomes. Statistical analyses applied were student t , Fisher exact and I 2 tests. Patients were devided into 6 groups according to treatment of choices: transarterial chemoembolization (TACE), surgery, radiotherapy, chemotherapy, interventional treatment and supportive care. Results: The overall survival rate of this cohort was 40.8%. The survival rate of patients receiving TACE was 33.3% and that of surgical patients was 41.9%. The survival time of patients with TACE was longer than surgical patients, but lack of a statistical significance. Patients had a follow-up of 15.7±16.6 (median 10) months. The patients receiving radiotherapy had the longest follow-up among all groups. Intra- and/or extrahepatic recurrence of hepatocellular carcinoma was the major mobidity. The mortality rates in a decremental sequence for patients receiving different treatments were supportive care >radiotherapy >surgery >TACE >interventional treatment. No difference was found in mortality between patients reported from case reports and those from non-case reports. Conclusions: Even though advanced hepatocellular carcinoma with right atrial thrombus is an aggressive malignancy, the the present study showed that patients’ prognosis was improved and survival time elongated with active treatments such as TACE and surgery. The present systematic review reveals improved outcomes with active treatments against conservative treatments.

Low-intensity pulsed ultrasound (LIPUS) with an intensity (spatial average temporal average, ISATA) of 30 mW/cm2 has been widely proved to be effective on impaired bone healing, but showing little effectiveness in the treatment of osteoporosis. We hypothesized that the intensity of LIPUS may be a key factor in explaining this difference, thus two intensity levels, the widely used 30 mW/cm2 and a higher 150 mW/cm2, were used to simultaneously treat osteoporosis and osteoporotic bone defect in ovariectomized (OVX) rats with a 1-mm drill hole on their left femurs. Results showed that 150 mW/cm2 LIPUS augmented the healing rate of the drill hole than 30 mW/cm2 after 3-week LIPUS treatment, although did not further enhance the healing rate after 6-week LIPUS treatment. For ameliorating osteoporosis, 150 mW/cm2 LIPUS achieved more advantages over 30 mW/cm2 in improving bone density, microstructure and biomechanics 6 weeks after LIPUS intervention. In conclusion, LIPUS with an intensity of 30 mW/cm2 was sufficient to facilitate bone defect healing, but a higher intensity can be considered as a rapid trigger for osteoporotic bone repair. In addition, improving the intensity of LIPUS may be a potentially effective consideration for alleviation of osteoporosis, and the LIPUS regimen in the treatment of osteoporosis remains to be optimized.

Busulfan is a chemotherapeutic agent used to treat chronic myelogenous leukemia and other myeloproliferative disorders. Increasing evidence has demonstrated that busulfan may induce testicular dysfunction by targeting genes that are expressed in the testis. Here, we showed that spermidine/spermine N1-acetyltransferase 2 (Sat2) was present in testicular Sertoli cells, and its expression was significantly increased by busulfan treatment. To investigate the implications of Sat2 upregulation for cell growth and function, a Sat2-overexpressing TM4 Sertoli cell model was established. Increased Sat2 expression led to inhibited cell proliferation and arrested cell cycle. Based on iTRAQ proteomics analysis, we revealed that Sat2 overexpression is detrimental to cell cycle progression and cell communication, and notably, Sat2 may disturb protein metabolic processes by altering translation regulation and protein complex subunit organization. In summary, the present study provides evidence that Sat2 upregulation induces alterations in the growth and function of Sertoli cells. In testis tissue subjected to busulfan, increased expression of Sat2 can cause cellular injury and subsequent organ damage, which could lead to male infertility. Therefore, Sat2 may be a novel molecular target for treating busulfan-induced testicular toxicity.

Injuries to the posterolateral corner of the knee can lead to chronic degenerative changes, external rotation instability, and varus instability if not repaired adequately. A proximal fibula avulsion fracture, referred to as an arcuate fracture, has been described in the literature, but a definitive repair technique has yet to be described. The objective of this study was to present a novel arcuate fracture repair technique, using a spiked-washer with an intramedullary screw, and to compare its biomechanical integrity to a previously described suture and bone tunnel method.Ten fresh-frozen cadaveric knees underwent a proximal fibula osteotomy to simulate a proximal fibula avulsion fracture. The lateral knee capsule and posterior cruciate ligament were also sectioned to create maximal varus instability. Five fibulas were repaired using a novel spiked-washer technique and the other 5 were repaired using the suture and bone tunnel method. The repaired knees were subjected to a monotonic varus load using a mechanical testing system instrument until failure of the repair or associated posterolateral corner structures.Compared with the suture repair group, the spiked-washer repair group demonstrated a 100% increase in stiffness, 100% increase in yield, 110% increase in failure force, and 108% increase in energy to failure.The spiked-washer technique offers superior quasi-static biomechanical performance compared with suture repair with bone tunnels for arcuate fractures of the proximal fibula. Further clinical investigation of this technique is warranted and the results of this testing may lead to improved outcomes and patient satisfaction for proximal fibula avulsion fractures.

Heat shock proteins (Hsps) are critical for cell survival under adverse environmental conditions. Bicyclol is a novel hepatoprotectant that has been shown to protect against liver injury by inducing Hsps, including Hsp27 and Hsp70. Although the role of Hsp70 in protecting against acute hepatic failure has been clearly explored, the precise function of Hsp27 in this setting is poorly defined. This study was undertaken to evaluate the role of Hsp27 in bicyclol-mediated hepatoprotection. Both primary hepatocytes and bone marrow-derived macrophages were subjected to bicyclol treatment, followed by detection of Hsp27 expression. Adenoviruses containing the mouse Hsp27 coding sequence or shRNA interference sequence targeting Hsp27 were used to manipulate Hsp27 expression in the liver before the mice were treated with bicyclol and/or confronted with D-galactosamine/lipopolysaccharide (Galn/LPS)-induced acute liver damage. Only hepatocytes increased their Hsp27 expression after bicyclol treatment and the time course of bicyclol-induced Hsp27 expression in hepatocytes was in line with the in vivo results. Although high-dose bicyclol could protect against liver failure without Hsp27, the effect of bicyclol given at a low dose was dependent on Hsp27 induction. Adenovirus-mediated transduction of Hsp27 protected against acute liver damage and partially replicated the protective effect afforded by bicyclol. These results demonstrated that bicyclol induced Hsp27 expression in hepatocytes, which was essential to bicyclol-mediated hepatoprotection. Overexpression of Hsp27 in hepatocytes could confer remarkable protection against acute liver damage.

Transforming growth factor β1(TGF-β1)/Smad3 pathway promotes the pathological progression of subchondral bone in osteoarthritis. The aim of this study is to determine the effect of low-intensity pulsed ultrasound (LIPUS) on the pathological progression and TGF-β1/Smad3 pathway of subchondral bone in temporomandibular joint osteoarthritis (TMJOA). Rabbit TMJOA model was established by type II collagenase induction. The left joint in this model was continuously stimulated with LIPUS for 3 and 6 weeks (1 MHz; 30 mW/cm2 ) for 20 min/day. The morphological and histological features of subchondral bone were respectively examined by microcomputed tomography and Safranin-O staining. The number of osteoclasts was quantitatively assessed by tartrate-resistant acid phosphatase staining. Immunohistochemistry and Western blot analysis were conducted to evaluate the protein expression of Cathepsin K and TGF-β1/Smad3 pathway. The results indicated that LIPUS could improve the trabecular microstructure and histological characteristics of subchondral bone in rabbit TMJOA. It also suppressed abnormal subchondral bone resorption and activation of TGF-β1/Smad3 pathway, characterized by the number of osteoclasts, protein expression levels of Cathepsin K, TGF-β1, type II TGFβ receptor, and phosphorylated Smad3 (pSmad3) were decreased. In conclusion, LIPUS promoted the quality of subchondral bone by suppressing osteoclast activity and TGF-β1/Smad3 pathway in rabbit TMJOA.

Prolonged mechanical unloading in bed-ridden patients and concurrent hormonal dysregulation represents the cause of one of the most severe forms of osteoporosis, a condition for which there are very few efficacious interventions available to date. Sclerostin, a Wnt antagonist, acts as a negative regulator of bone formation. Sclerostin antibody–mediated blockade of sclerostin can dramatically enhance bone formation and reduce bone resorption. This study was designed to investigate the therapeutic effect of the sclerostin antibody (Scl-Ab) on severe bone loss induced by concurrent mechanical unloading and estrogen deficiency in a hindlimb-suspended and ovariectomized rat model, and to study the cellular mechanisms underlying severe osteoporosis and Scl-Ab action. Unloading and ovariectomy resulted in severe loss of trabecular and cortical bone mass and strength; Scl-Ab can significantly counteract the deterioration of bone in unloaded and/or ovariectomized rats, with noticeably increased cortical bone formation. Scanning electron microscopy analysis revealed that unloading and ovariectomy lead to multiple morphological and structural abnormalities of osteocytes in cortical bone and the abnormalities were abolished by Scl-Ab administration. This study extends our previous conclusion that Scl-Ab represents a promising therapeutic approach for the severe bone loss that occurs after being exposed to estrogen deficiency and prolonged mechanical unloading.

Aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism is an established genetic risk of hypertension, diabetes, and coronary heart diseases in Asian population. Previous experimental data showed ALDH2 regulated inflammation, a potential mechanism of heart failure with preserved ejection fraction (HFpEF). However, clinically, the association between ALDH2 polymorphism and incidence of HFpEF remains unknown. In this prospective cross-sectional study, ALDH2 genotyping was performed in 613 consecutive patients enrolled with cardiovascular diseases (CVDs), including hypertension, coronary heart diseases, and/or diabetes mellitus, with normal left ventricular ejection fraction (LVEF). HFpEF was diagnosed according to symptoms and/or signs of dyspnea, fatigue or ankle swelling, N-terminal pro-B-Type natriuretic peptide (NT pro-BNP ≥ 280 pg/mL), LVEF ≥ 50%, and at least one additional criterion: left atrial enlargement (left atrial diameter > 40 mm), diastolic dysfunction (E/E’ ≥ 13 or E’/A’

Staphylococcus aureus is a well-known organism which is responsible for a variety of human infectious diseases including skin infections, pneumonia, bacteremia, and endocarditis. Few of the microorganisms can be transmitted from mother to the newborn or infant by milk breastfeeding. This study aims to identify transmission of S. aureus from healthy, lactating mothers to their infants by breastfeeding. Stool specimens of diarrheal infants and breast milk of their mother (totally three pairs) were collected and six Staphylococcus aureus isolates were cultured positively. Homology and molecular characters of isolated strains were tested using pulsed-field gel electrophoresis (PFGE), spa typing, and multilocus sequence typing. Furthermore, toxin genes detection was also performed. Each pair of isolates has the same PFGE type and spa type. Four Sequence types (STs) were found among all the isolates; they are ST15, ST188, and ST59, respectively. Among the strains, seb, sec, and tst genes were found, and all were negative for pvl gene. The homology of the S. aureus strains isolated from the infants' stool and the mothers' milk was genetically demonstrated, which indicated that breastfeeding may be important in the transmission of S. aureus infection, and the character of S. aureus needed to be further evaluated.

Osteoporosis is characterized by low bone mass and compromised trabecular architecture, and is commonly occurred in post-menopausal women with estrogen deficiency. In addition, prolonged mechanical unloading, i.e., long term bed rest, can exaggerate the bone loss. Sclerostin is a Wnt signaling antagonist and acts as a negative regulator for bone formation. A sclerostin-neutralizing antibody (Scl-Ab) increased bone mineral density in women with postmenopausal osteoporosis and healthy men. The objective of this study was to characterize the condition of bone loss in ovariectomized (OVX) rats with concurrent mechanical unloading and evaluate the effect of sclerostin antibody treatment in mitigating the prospective severe bone loss conditions in this model. Four-month-old OVX- or sham-operated female SD rats were used in this study. They were subjected to functional disuse induced by hind-limb suspension (HLS) or free ambulance after 2days of arrival. Subcutaneous injections with either vehicle or Scl-Ab at 25mg/kg were made twice per week for 5weeks from the time of HLS. μCT analyses demonstrated a significant decrease in distal metaphyseal trabecular architecture integrity with HLS, OVX and HLS+OVX (bone volume fraction decreased by 29%, 71% and 87% respectively). The significant improvements of various trabecular bone parameters (bone volume fraction increased by 111%, 229% and 297% respectively as compared with placebo group) with the administration of Scl-Ab are associated with stronger mechanical property and increased bone formation by histomorphometry. These results together indicate that Scl-Ab prevented the loss of trabecular bone mass and cortical bone strength in OVX rat model with concurrent mechanical unloading. The data suggested that monoclonal sclerostin-neutralizing antibody represents a promising therapeutic approach for severe osteoporosis induced by estrogen deficiency with concurrent mechanical unloading.

Osteoporosis is a musculoskeletal disease which is mainly characterized by bone loss and deterioration of bone microstructure, to which the middle-aged and elderly people are susceptible. It is often accompanied with bone pain, humpback, fractures and other symptoms, seriously affecting the quality of life of patients. As the population ages, osteoporosis incidence is increasing year by year, and currently these are approximately 200 million patients suffered from osteoporosis in the whole world. Furthermore, osteoporotic fracture has also caused great economic burden to families and society. On the other hand, in the weightless space environment, osteoporosis induced by unloading bones has become one of the important problems of astronauts’ health, leading to impair their space exploration ability enhancement. Hence it is of great significance to its early diagnosis and timely treatment. Ultrasound as a therapeutic method has the advantage of low cost, non-invasive, non-ionizing radiation, fast and can be carried, and the findings in recent years show that ultrasonic backscatter signals can effectively reflect the micro-structure information of cancellous bone, therefore the evaluation of cancellous bone and diagnosis of osteoporosis with ultrasonic backscatter signal has become a focus. And clinical evaluation of bone has made significant progress in adults and newborns. Currently, the main treatment of osteoporosis is drug therapy (common used drugs are bisphosphonates, calcium, vitamin D, calcitonin, estrogen). Drug therapy typically has systemic effects along with side effects, however. Physical therapy such as ultrasound, magnetic therapy and hyperthermia is able to avoid the adverse effect of drug therapy. Low-intensity pulsed ultrasound (LIPUS) has been proved to be an effective mechanical signal to bone tissue and it is used to the treatment of orthopedic diseases, which can play its mechanical effect and avoid the damage of thermal effect to the tissue cells. Study in recent years has demonstrated that LIPUS with certain parameters plays a positive role in the progress of fracture healing, it can promote cell proliferation and differentiation, accelerate calcium mineralization and regulate gene expression and cell growth factors associated with bone tissue cells release, so as to accelerate the progress of bone formation and effectively shorten the healing time. Osteoporosis is a kind of bone disease with main feature of bone mass loss and it is reasonable to consider that the treatment of osteoporosis has the similar physiological mechanism as fracture healing, thus it may be an important potential means of osteoporosis treatment. By referring to numerous documentations related to “LIPUS”, “fracture”, “osteoporosis”, this article begins from the bone structure and function, biological mechanisms of LIPUS treatment for orthopedic diseases and experimental methods of LIPUS treatment for osteoporosis to analyze and demonstrate the effective basis for LIPUS treatment of osteoporosis and review the current study situation of LIPUS treatment for osteoporosis, so as to provide theoretical evidences and new ideas for treatment of osteoporosis.

Background Despite recognised benefits of optimal glycaemic control in patients with type 1 diabetes mellitus (T1DM), good control is still difficult to achieve, particularly for adolescents and young adults. Recognition of factors that may assist early optimisation of glycaemic control is therefore important. Aims We explored associations of demographic, social and behavioural factors with glycosylated haemoglobin (HbA1c) levels in participants with T1DM aged 18-25 years. Methods A cross-sectional analysis was performed on young adults attending a dedicated multidisciplinary clinic at Fremantle Hospital, Western Australia from January to August 2014. Results Data from 93 participants were analysed. Mean age was 21.4 ± 2.3 years, and 39.8% of the cohort were female. Longer duration of diabetes was associated with higher HbA1c (r = 0.25, P = 0.04). Men had lower HbA1c than women (8.2 ± 1.6 vs 9.2 ± 2.0%, P = 0.01). Increased frequency of clinic attendance was associated with lower HbA1c (r = -0.27, P = 0.02). Those engaged in work or study had better HbA1c compared with those who were not (8.9 ± 2.1 vs 10.5 ± 2.1%, P = 0.03). Socioeconomic disadvantage, risk-taking behaviour, insulin pump use and distance travelled to clinic were not associated with differences in HbA1c. Conclusion In young adults with T1DM, geographical separation, socioeconomic disadvantage and risk-taking behaviours did not influence glycaemic control. Longer duration of diabetes identifies young adults at higher risk of poor control, while attendance at a multidisciplinary clinic and engagement in work or study was associated with better glycaemic control. Additional studies are warranted to clarify the role of behavioural interventions to improve diabetes management in young adults.

A cardiovascular stent is a small mesh tube that expands a narrowed or blocked coronary artery. Unfortunately, current stents, regardless metallic or polymeric, still largely fall short to the ideal clinical needs due to late restenosis, thrombosis and other clinical complications. Nonetheless, metallic stents are preferred clinically thanks to their superior mechanical property and radiopacity to their polymeric counterparts. The emergence of bioresorbable metals opens a window for better stent materials as they may have the potential to reduce or eliminate late restenosis and thrombosis. In fact, some bioresorbable magnesium (Mg)-based stents have obtained regulatory approval or under trials with mixed clinical outcomes. Some major issues with Mg include the too rapid degradation rate and late restenosis. To mitigate these problems, bioresorbable zinc (Zn)-based stent materials are being developed lately with the more suitable degradation rate and better biocompatibility. The past decades have witnessed the unprecedented evolution of metallic stent materials from first generation represented by stainless steel (SS), to second generation represented by Mg, and to third generation represented by Zn. To further elucidate their pros and cons as metallic stent materials, we systematically evaluated their performances in vitro and in vivo through direct side-by-side comparisons. Our results demonstrated that tailored Zn-based material with proper configurations could be a promising candidate for a better stent material in the future.

Cross section area (CSA) of spinal canal has been a crucial indicator for lumbar spinal stenosis (LSS), which remains the leading preoperative diagnosis for elder people. Recently, the machine learning algorithms have been investigated in[7-10] for automatic classification systems. The methods investigated in[7-10] exploited the characteristics of cerebrospinal fluid (CSF) in T1 and T2 sequences of MRI images. Nevertheless, in order to apply the trained classifiers, the differences among images need to be as small as possible due to the nature of classification. To address the issue, this paper reinvented the wheel to propose unsupervised segmentation method without requirement of training process. Based on the characteristic property of skewness, the proposed algorithm can also distinguish the finer details such as nerve roots from CSF. The experimental study further demonstrated the benefits of proposed framework.

Objectives The serum concentration of brain-derived neurotrophic factor (BDNF) was compared among patients with Parkinson’s disease (PD), patients with essential tremor (ET), and healthy participants, and its association with clinical features of PD and ET was assessed. Methods Demographic and clinical data were collected from 60 patients with PD at different clinical stages, 60 patients with ET, and 60 controls. All participants’ serum BDNF concentrations were measured. Their motor abilities and activity were assessed by the Unified PD Rating Scale and the Hoehn and Yahr (H-Y) staging scale. Results Serum BDNF was significantly lower in patients with PD than in patients with ET and controls. BDNF decreased only in the early disease stages (H-Y stages I and II), but increased markedly in the advanced stages (H-Y stages III–V). There was no significant difference between patients with ET and controls. The BDNF concentration was negatively correlated with age at PD onset and positively associated with disease duration, severity of PD symptoms, and treatment with L-DOPA. Conclusions A low serum BDNF concentration may serve as a biomarker in the early stages of PD, whereas a high concentration with PD progression may be due to treatment with L-DOPA in the advanced stages.

Background: Osteoporosis parallels aging and functional mechanical unloading (e.g., space flight and bed rest), jeopardizing mineral density, microstructure, and integrity of bone and leading to an increased risk of fracture. A way to combat this deterioration is to harness the sensitivity of bone to mechanical signals. Objective: This study evaluates the longitudinal effect of a dynamic mechanical loading through the heel on human bone in vivo during 90-day bed rest, monitored by quantitative ultrasound (QUS) imaging and dual-energy X-ray absorptiometry (DXA) in localized regions of interests, i.e., calcaneus. Methods: A total of 29 bed rest individuals were evaluated (11 control and 18 treatment) with a brief (10-minute) daily low-intensity (0.3g), high-frequency (30Hz) dynamic mechanical stimulation countermeasure through vibrational inhibition bone erosion (VIBE). Both QUS and DXA detected longitudinal bone density and quality changes. Results: Ultrasound velocity (UV) decreased in the control group and increased in the group treated with low-intensity loading. The UV increased by 1.9% and 1.6% at 60- and 90-day bed rest (p=0.01) in VIBE over control groups. A trend was found in broadband ultrasound attenuation (BUA), with a VIBE benefit of 1.8% at day 60 and 0.5% at day 90 in comparison with control (p=0.5). Bone mineral density (BMD) assessed by DXA decreased -4.50% for control individuals and -2.18% for VIBE individuals, showing a moderate effect of the mechanical intervention (p=0.19). Significant correlations between QUS and DXA were observed, with a combined BUA and UV vs. BMD: r2=0.70. Conclusion: These results indicated that low-intensity, high-frequency loading has the potential to mitigate regional bone loss induced by long-term bed rest and that QUS imaging may be able to assess the subtle changes in bone alteration. Translational potential of this article: Quantitative ultrasound has shown the efficacy of noninvasively assessing bone mass and structural properties in cadaver and isolated trabecular bone samples. While its ability in measuring in vivo bone quality and density is still unclear, a scanning confocal ultrasound imaging is developed and can perform an instant assessment for the subtle changes of such bone loss. This ultrasound imaging modality can potentially be used in the clinical assessment of bone mass. Moreover, physical stimulation has shown the ability to prevent bone loss induced by functional disuse and estrogen deficiency in animal models. However, its treatment capability is unclear. This study has shown that low-magnitude mechanical signals, introduced using low-intensity vibration (LIV), can mitigate regional bone loss caused by functional disuse. Thus localized mechanical treatment, and the quantitative ultrasound imaging have shown translational potential to noninvasively attenuate bone loss, and assess bone mass in the clinic, e.g., in an extreme condition such as long-term space mission, and long-term bedrest such as in case of spinal cord injury. Keywords: Bed rest, Bone remodelling, Confocal acoustic navigation, Osteoporosis and osteopenia, Ultrasound imaging, Whole-body vibration

Objective: To get a comprehensive understanding about the relationship between obstructive sleep apnea (OSA) and asthma by reviewing the epidemiology, pathophysiology, and clinical manifestation and then summarizing the latest progress on diagnosis and treatment. Data Sources: Articles referred in this review were mainly collected from a comprehensive search of the PubMed published in English from 1990 to 2015 with the terms OSA and asthma as the main keywords. Highly regarded older publications were also included. Study Selection: Information about the features of the two diseases in common, the pathophysiologic association between them and their current treatments from the literature search were identified, retrieved, and summarized. Results: Both OSA and asthma are very prevalent conditions. The incidences of them have kept on rising in recent years. Asthma is often accompanied by snoring and apnea, and OSA often combines with asthma, as well. They have many predisposing and aggravating factors in common. Possible shared direct mechanistic links between them include mechanical effects, intermittent hypoxia, nerve reflex, inflammation, leptin, etc. Indirect mechanistic links include medication, nose diseases, smoking, obesity, and gastroesophageal reflux disease. Since OSA presents many similar features with nocturnal asthma, some scholars termed them as a sole syndrome - alternative overlap syndrome, and proved that asthma symptoms in those patients could be improved through the treatment of continuous positive airway pressure. Conclusions: OSA and asthma are closely associated in pathogenesis, symptoms, and therapies. With the growing awareness of the relationship between them, we should raise our vigilance on the coexistence of OSA in those difficult-to-control asthmatic patients. Further studies are still needed to guide the clinical works.

Context Thyroid hormones modulate proliferative, metabolic and angiogenic pathways. However few studies have examined associations of thyroid hormones with cancer risk. Objectives To explore associations of thyrotropin (TSH), free thyroxine (FT4) and anti-thyroperoxidase antibodies (TPOAb) with the incidence of all (non-skin) cancers and specific common cancers. Design and setting A prospective cohort study of a community-dwelling population aged 25–84 years in Western Australia. Main outcome measures Archived sera from 3649 participants in the 1994/1995 Busselton Health Survey were assayed for TSH, FT4 and TPOAb. Cancer outcomes until 30 June 2014 were ascertained using data linkage. Longitudinal analyses were performed using Cox proportional hazards regression. Results During 20-year follow-up, 600 participants were diagnosed with non-skin cancer, including 126, 100, 103 and 41 prostate, breast, colorectal and lung cancers respectively. Higher TSH was associated with a lower risk of prostate cancer after adjusting for potential confounders, with a 30% lower risk for every 1 mIU/L increase in TSH (adjusted hazard ratio (HR): 0.70, 95% confidence interval (CI): 0.55–0.90, P = 0.005). Similarly, higher FT4 was associated with an increased risk of prostate cancer (adjusted HR: 1.11 per 1 pmol/L increase, 95% CI: 1.03–1.19, P = 0.009). There were no associations of TSH, FT4 or TPOAb with all non-skin cancer events combined, or with breast, colorectal or lung cancer. Conclusion In a community-dwelling population, lower TSH and higher FT4 were associated with an increased risk of prostate cancer. Further studies are required to assess if thyroid function is a biomarker or risk factor for prostate cancer.

The aim of this research is to apply an approach based on phase transfer entropy (PTE) and graph theory to study the interactions between the stereo-electroencephalography (SEEG) activities recorded in multilobar origin, in order to evaluate their ability to detect the epileptogenic zone (EZ) of temporal lobe epilepsies (TLE). Forty-three patients were included in this retrospective study. Five to sixteen (median = 12) multilead electrodes were implanted per patient, and, for each patient, a sub-set of between 10 and 32 (median = 22) bipolar derivations was selected for analysis. The leads were classified into the onset leads (OLs), the early propagation leads (EPLs), and the rest of the leads (RLs). The results showed that a significantly different dynamic trend of the out/in ratio (more obvious in the gamma band) distinguishes the OLs from RLs in the 23 patients who were seizure-free not only during the ictal event (significant elevation), but also during the inter-,pre-, late-ictal periods, and especially in the post-ictal (sharp decline) state. However, in the 20 patients who were not-seizure-free, the differences between the OLs and RLs during the post-ictal period were not found in any frequency band. The dynamic trend was used to predict surgical outcome, and the results showed that the sensitivity was 91% and the specificity was 70%. In brief, this study indicates that our approach may add new and valuable information, providing efficient quantitative measures useful for localizing the EZ., Highlights • Temporal lobe epilepsy (TLE) is thought to be a network disease. • Dynamic trend of out/in ratio of the onset leads was different from the other leads. • Postictal sharp decline of out/in ratio in gamma band is characteristic in EZ. • Spreading latency might not be the key discriminant factor of epileptogenicity. • A phase transfer entropy and graph theory based approach is valid to predict EZ.

Purpose: Our aim is to examine ictal onset patterns (IOPs), extratemporal early propagations (EPs) and inner relationship between them based on stereo-electroencephalography recordings in the patients with atypical temporal lobe epilepsy, and to evaluate their impact on seizure prognosis and cognitive outcomes after epilepsy surgery. Methods: Forty-three patients were included in this retrospective study. Five to sixteen multilead electrodes were implanted per patient. All of them underwent a standard craniotomy for tailored resection of the hypothetical epileptogenic zone. Post-operative seizure status and cognitive outcomes were evaluated by Engle’s classification, Wechsler intelligence and Wechsler memory scale. Results: Four types of IOPs were identified in the 43 patients. The patients with low frequency highamplitude periodic spikes (LFPS) and spike or poly-spike fast discharges (SpFD) had better seizure outcomes. There were ten patients with extratemporal EPs, who had worse clinical outcomes than those without extratemporal EPs (Engel’s class I: χ2 =10.689, p=0.001; Engel’s class Ia: χ2 =4.251, p=0.039). Three conditions related to IOPs and extratemporal EPs were combined to predict the seizure prognosis after operation. The sensitivity and specificity were 90.0% and 78.6% for Engel’s class I, and were 87.0% and 55.0% for Engel’s class Ia. The patients with LFPS showed more significant improvement in memory quotient (MQ) but not in full intelligence quotient (FIQ) than those with other IOPs. Conclusions: IOPs and extratemporal EPs are closely related to seizure status and cognitive outcomes after epilepsy surgery in atypical TLE patients.

Our previous study has shown that cerebral ischemic preconditioning (CIP) can up-regulate the expression of glial glutamate transporter-1 (GLT-1) during the induction of brain ischemic tolerance in rats. The present study was undertaken to further explore the uptake activity of GLT-1 in the process by observing the changes in the concentration of extracellular glutamate with cerebral microdialysis and high-performance liquid chromatography. The results showed that a significant pulse of glutamate concentration reached the peak value of sevenfold of the basal level after lethal ischemic insult, which was associated with delayed neuronal death in the CA1 hippocampus. When the rats were pretreated 2 days before the lethal ischemic insult with CIP which protected the pyramidal neurons against delayed neuronal death, the peak value of glutamate concentration decreased to 3.9 fold of the basal level. Furthermore, pre-administration of dihydrokainate, an inhibitor of GLT-1, prevented the protective effect of CIP on ischemia-induced CA1 cell death. At the same time, compared with the CIP + Ischemia group, the peak value of glutamate concentration significantly increased and reached sixfold of the basal level. These results indicate that CIP induced brain ischemic tolerance via up-regulating GLT-1 uptake activity for glutamate and then decreasing the excitotoxicity of glutamate.

Physical signals within the bone, i.e. generated from mechanical loading, have the potential to initiate skeletal adaptation. Strong evidence has pointed to bone fluid flow (BFF) as a media between an external load and the bone cells, in which altered velocity and pressure can ultimately initiate the mechanotransduction and the remodeling process within the bone. Load-induced BFF can be altered by factors such as intramedullary pressure (ImP) and/or bone matrix strain, mediating bone adaptation. Previous studies have shown that BFF induced by ImP alone, with minimum bone strain, can initiate bone remodeling. However, identifying induced ImP dynamics and bone strain factor in vivo using a non-invasive method still remains challenging. To apply ImP as a means for alteration of BFF, it was hypothesized that non-invasive dynamic hydraulic stimulation (DHS) can induce local ImP with minimal bone strain to potentially elicit osteogenic adaptive responses via bone–muscle coupling. The goal of this study was to evaluate the immediate effects on local and distant ImP and strain in response to a range of loading frequencies using DHS. Simultaneous femoral and tibial ImP and bone strain values were measured in three 15-month-old female Sprague Dawley rats during DHS loading on the tibia with frequencies of 1 Hz to 10 Hz. DHS showed noticeable effects on ImP induction in the stimulated tibia in a nonlinear fashion in response to DHS over the range of loading frequencies, where they peaked at 2 Hz. DHS at various loading frequencies generated minimal bone strain in the tibiae. Maximal bone strain measured at all loading frequencies was less than 8 μe. No detectable induction of ImP or bone strain was observed in the femur. This study suggested that oscillatory DHS may regulate the local fluid dynamics with minimal mechanical strain in the bone, which serves critically in bone adaptation. These results clearly implied DHS's potential as an effective, non-invasive intervention for osteopenia and osteoporosis treatments.

Disuse osteopenia has shown to decrease bone mineral density and compromise bone’s integrity, i.e., in aging population and long term functional disuse. The degree of attenuation of trabecular bone loss and deterioration of its microarchitecture is closely dependent on the mechanical loading parameters within the regimen. Dynamic muscle stimulation as a preventive countermeasure for disuse osteopenia has been shown to be effective. The objective of this study is to determine whether the contraction-to-rest ratio is a crucial parameter to affect the skeletal adaptive responses under a functional disuse environment. Fifty-six skeletally matured Sprague-Dawley rats were divided into seven groups for the 4-week experiment: baseline control, age-matched control, hindlimb suspended (HLS), and HLS plus muscle stimulation with a contraction-to-rest ratio of 1/4, 2/8, 4/6, and 2/28 sec. Muscle stimulation was carried out for total of 10 minutes per day, 5 days per week, for 4 weeks. Trabecular bone in the distal femurs was analyzed with microcomputed tomography and histomorphometry. HLS alone for 4-week resulted in a 25 – 45% trabecular bone loss in the distal femur. Dynamic muscle stimulation, applied at 50 Hz frequency, with a 2/8 sec contraction-to-rest ratio demonstrated significant attenuation of trabecular bone loss against the 4-week disuse, with up to +74% in bone volume fraction, +164% in connectivity, +20% in trabecular number, and −18% in spacing (p < 0.05). Stimulation with 1/4 and 4/6 also showed similar effects but with a lesser percentage differences when comparing to the HLS animals. Similarly, histomorphometric analysis showed partial enhancement in mineralizing surface and mineral apposition rate. The results suggested the potentials of dynamic muscle stimulation in regulating skeletal adaptive responses and illustrated the effects of optimized contraction-to-rest in mitigation of bone loss, in which 2/8 sec has shown maximal adaptive response among all tested ratios.

Intramedullary pressure (ImP) and low-level bone strain induced by oscillatory muscle stimulation (MS) has the potential to mitigate bone loss induced by disuse osteopenia, i.e., hindlimb suspension (HLS). To test this hypothesis, we evaluated (a) MS-induced ImP and bone strain as function of stimulation frequency and (b) the adaptive responses to functional disuse, and disuse plus 1 and 20 Hz stimulation in vivo. Femoral ImP and bone strain generated by MS were measured in the frequencies of 1-100 Hz in four rats. Forty retired breeder rats were used for the in vivo HLS study. The quadriceps muscle was stimulated at frequencies of 1 and 20 Hz, 10 min/d for four weeks. The metaphyseal trabecular bone quantity and microstructure at the distal femur were evaluated using microCT, while bone formation indices were analyzed using histomorphometric technique. Oscillatory MS generated a maximum ImP of 45+/-9 mmHg at 20 Hz and produced a maximum matrix strain of 128+/-19 microepsilon at 10 Hz. Our analyses from the in vivo study showed that MS at 20 Hz was able to attenuate trabecular bone loss and partially maintain the microstructure induced by HLS. Conversely, there was no evidence of an adaptive effect of stimulation at 1 Hz on disused skeleton. The results suggested that oscillatory MS regulates fluid dynamics and mechanical strain in bone, which serves as a critical mediator of adaptation. These results clearly demonstrated the ability of MS in attenuating bone loss from the disuse osteopenia, which may hold potential in mitigating skeletal degradation imposed by conditions of disuse, and may serve as a biomechanical intervention in clinic application.

Background The transplantation of bone marrow stromal cells (MSCs) has proved to ameliorate ischemic brain injury in animals, but most transplanted MSCs undergo apoptosis in the ischemic penumbra, greatly compromising the therapeutic value of this treatment. Meanwhile, cell apoptosis can be inhibited by post-ischemia exercise which has been demonstrated to improve the expression of related anti-apoptotic proteins. The present study investigated whether treadmill exercise enhances the neuroprotective effects of transplanted MSCs in a rat experimental stroke model. Result Rats were subjected to 2-h middle cerebral artery occlusion (MCAO). Twenty-four hours after reperfusion, they were assigned randomly to receive no MSCs treatment and no exercise (control group), intravenous transplantation of MSCs and treadmill exercise (MSCs + Ex group), MSCs transplantation only (MSCs group) and treadmill exercise only (Ex group). Neurological assessment, TUNEL staining and western blot were performed. Compared with the MSCs group and Ex group, the MSCs + Ex group reported markedly improved neurological function, significantly decreased apoptotic cells, and increased expressions of survivin and bcl-2 (p

Granular cell tumor is rare and accounts for approximately 0.5 % of all soft tissue tumors. The malignant granular cell tumor, especially cutaneous malignant granular cell tumor is extremely rare. The present case is the first patient of primary cutaneous malignant granular cell tumor reported from China in English. A review of the literature is performed, and the presentation, position, pathological diagnosis, treatment and prognosis of the patients with cutaneous malignant granular cell tumor of the reported cases before is analysed.

We assessed the local distribution of bone mechanical properties on a micro-nano-scale and its correlation to strain distribution. Left tibia samples were obtained from 5-month old female Sprague Dawley rats, including baseline control (n=9) and hindlimb suspended (n=9) groups. Elastic modulus was measured by nanoindentation at the dedicated locations. Three additional tibias from control rats were loaded axially to measure bone strain, with 6-10N at 1Hz on a Bose machine for strain measurements. In the control group, the difference of the elastic modulus between periosteum and endosteum was much higher at the anterior and posterior regions (2.6GPa), where higher strain differences were observed (45μɛ). Minimal elastic modulus difference between periosteum and endosteum was observed at the medial region (0.2GPa), where neutral axis of the strain distribution was oriented with lower strain difference (5μɛ). In the disuse group, however, the elastic modulus differences in the anterior posterior regions reduced to 1.2GPa from 2.6GPa in the control group, and increased in the medial region to 2.7GPa from 0.2GPa. It is suggested that the remodeling rate in a region of bone is possibly influenced by the strain gradient from periosteum to endosteum. Such pattern of moduli gradients was compromised in disuse osteopenia, suggesting that the remodeling in distribution of micro-nano-elastic moduli among different regions may serve as a predictor for early stage of osteoporosis.

Quantitative ultrasound (QUS) assessment, including broadband ultrasound attenuation (BUA), is an efficient technique for assessing bone quality in various statuses, e.g., osteoporosis. While assessing trabecular bone loss is essential to bone quality, the existence of cortical bone can substantially reduce the accuracy of BUA measurement. In this study, we developed an approach to quantify the influence of the cortical end-plate in the QUS on 18 cadaver calcanei using both analytical and experimental analyses. A simplified cortical-trabecular-cortical sandwich model has been developed for simulation of wave propagations. Results show that the cortical end-plate has a significant effect on BUA (yielding 8.5 +/- 3.6 dB/MHz in cortical bone alone), approximately 15% of the BUA value over the whole bone BUA measurement (54.1 +/- 20.1 dB/MHz). The phenomenon has been predicted by the developed analytical model with a high correlation (r2 = 0.63, p0.0001). The data have suggested that the mechanism of the BUA attributed to the cortical end-plate is primarily due to the ultrasonic wave transmission and reflection within the cortical layers. Therefore, the influence of the cortical end-plate in BUA can be quantified and incorporated into the QUS assessment for bone quality, which may provide insight into BUA measurement for accurate diagnosis of bone diseases.

Interstitial bone fluid flow (IBFF) is suggested as a communication medium that bridges external physical signals and internal cellular activities in the bone, which thus regulates bone remodeling. Intramedullary pressure (ImP) is one main regulatory factor of IBFF and bone adaptation related mechanotransduction. Our group has recently observed that dynamic hydraulic stimulation (DHS), as an external oscillatory muscle coupling, was able to induce local ImP with minimal bone strain as well as to mitigate disuse bone loss. The current study aimed to evaluate the dose dependent relationship between DHS's amplitude, i.e. , 15 and 30 mmHg, and in vivo ImP induction, as well as this correlation on bone's phenotypic change. Simultaneous measurements of ImP and DHS cuff pressures were obtained from rats under DHS with various magnitudes and a constant frequency of 2 Hz. ImP inductions and cuff pressures upon DHS loading showed a positively proportional response over the amplitude sweep. The relationship between ImP and DHS cuff pressure was evaluated and shown to be proportional, in which ImP was raised with increases of DHS cuff pressure amplitudes (R 2 = 0.98). A 4-week in vivo experiment using a rat hindlimb suspension model demonstrated that the mitigation effect of DHS on disuse trabecular bone was highly dose dependent and related to DHS's amplitude, where a higher ImP led to a higher bone volume. This study suggested that sufficient physiological DHS is needed to generate ImP. Oscillatory DHS, potentially induces local fluid flow, has shown dose dependence in attenuation of disuse osteopenia.

Disuse osteopenia and bone loss have been extensively reported in long duration space mission and long term bed rest. The pathology of the bone loss is similar to osteoporosis but highly confined to weight bearing bones. The current anabolic and/or anti-resorptive drugs have systemic effects and are costly over extended time, with concerns of long term fracture risk. This study use Low Intensity Pulsed Ultrasound (LIPUS) as a non-invasive acoustic force and anabolic stimulus to countermeasure disuse induced bone loss. Four-month old C57BL/6 mice were randomized to five groups, 1) age-matched (AM), 2) non-suspended sham (NS), 3) nonsuspended –LIPUS (NU), 4) suspended sham (SS), and 5) suspended-LIPUS (SU) groups. After four weeks of suspension, µCT analyses showed significant decreases in trabecular bone volume fraction (BV/TV) (−36%, p

Stress fractures have been proposed to arise from repetitive activity of training inducing an accumulation of microfractures in locations of peak strain. However, stress fractures most often occur long before accumulation of material damage could occur; they occur in cortical locations of low, not high, strain; and intracortical osteopenia precedes any evidence of micro-cracks. We propose that this lesion arises from a focal remodeling response to site-specific changes in bone perfusion during redundant axial loading of appendicular bones. Intramedullary pressures significantly exceeding peak arterial pressure are generated by strenuous exercise and, if the exercise is maintained, the bone tissue can suffer from ischemia caused by reduced blood flow into the medullary canal and hence to the inner two-thirds of the cortex. Site specificity is caused by the lack, in certain regions of the cortex, of compensating matrix-consolidation-driven fluid flow which brings nutrients from the periosteal surface to portions of the cortex. Upon cessation of the exercise, re-flow of fresh blood into the vasculature leads to reperfusion injury, causing an extended no-flow or reduced flow to that portion of the bone most strongly denied perfusion during the exercise. This leads to a cell-stress-initiated remodeling which ultimately weakens the bone, predisposing it to fracture.

The daily stress stimulus theory of bone adaptation was formulated to describe the loading conditions necessary to maintain bone mass. This theory identifies stress/strain magnitude and loading cycle number as sufficient to define an appropriate maintenance loading signal. Here, we extend the range over which loading cycle number has been evaluated to determine whether the daily stress stimulus theory can be applied to conditions of very high numbers of loading cycles at very low strain magnitudes. The ability of a relatively high-frequency (30-Hz) and moderate-duration (60-minute) loading regimen to maintain bone mass in a turkey ulna model of disuse osteopenia was evaluated by correlating the applied strain distributions to site-specific remodeling activity. Changes in morphology were investigated following 8 weeks of disuse compared with disuse plus daily exposure to 108,000 applied loading cycles sufficient to induce peak strains of approximately 100 microstrain. A strong correlation was observed between the preservation of bone mass and longitudinal normal strain (R = 0.91) (p < 0.01). The results confirm the strong antiresorptive influence of mechanical loading and identify a threshold near 70 microstrain for a daily loading cycle regimen of approximately 100,000 strain cycles. These results are not consistent with the daily stress stimulus theory and suggest that the frequency or strain rate associated with the loading stimulus must also play a critical role in the mechanism by which bone responds to mechanical strain.

Microgravity induced bone loss represents a critical health problem in astronauts, particularly occurred in weight-supporting skeleton, which leads to osteopenia and increase of fracture risk. Lack of suitable evaluation modality makes it difficult for monitoring skeletal status in long term space mission and increases potential risk of complication. Such disuse osteopenia and osteoporosis compromise trabecular bone density, and architectural and mechanical properties. While X-ray based imaging would not be practical in space, quantitative ultrasound may provide advantages to characterize bone density and strength through wave propagation in complex trabecular structure. This study used a scanning confocal acoustic diagnostic and navigation system (SCAN) to evaluate trabecular bone quality in 60 cubic trabecular samples harvested from adult sheep. Ultrasound image based SCAN measurements in structural and strength properties were validated by μCT and compressive mechanical testing. This result indicated a moderately strong negative correlations observed between broadband ultrasonic attenuation (BUA) and μCT-determined bone volume fraction (BV/TV, R2=0.53). Strong correlations were observed between ultrasound velocity (UV) and bone's mechanical strength and structural parameters, i.e., bulk Young's modulus (R2=0.67) and BV/TV (R2=0.85). The predictions for bone density and mechanical strength were significantly improved by using a linear combination of both BUA and UV, yielding R2=0.92 for BV/TV and R2=0.71 for bulk Young's modulus. These results imply that quantitative ultrasound can characterize trabecular structural and mechanical properties through measurements of particular ultrasound parameters, and potentially provide an excellent estimation for bone's structural integrity.

Stephen Jay Gould’s commentary on Darwinism emphasizes the vital importance of an organism’s ability to adapt effectively to changing signals arising from the environment. Pressure, gravity, waves, temperature, light, electric, and magnetic fields make up an omnipresent physical presence since the beginning of time. It should be no surprise, therefore, that the capacity of biologic systems to adapt to physical signals is a common attribute for essentially all life, including bacteria, yeast, plant, and animal cells, and that the cellular machinery responsible for sensing and responding to mechanical signals evolved during billions of years of exposure to a range of physical challenges. The evolutionary success of any organism has always been based on its ability to accommodate, acclimate, and adapt to changes in its immediate temporal and spatial environment. It should not be difficult to recognize that the primacy of vertebrates through the past 500 million years has been achieved through highly orchestrated adaptation to physical signals. Thus, if physical signals could be harnessed to prevent or reverse the age-, injury-, or disease-related deterioration of the musculoskeletal system, it would diminish dependence on pharmacologic agents prescribed for these goals.

Osteoblasts are derived from mesenchymal stem cells (MSCs), which initiate and regulate bone formation. New strategies for osteoporosis treatments have aimed to control the fate of MSCs. While functional disuse decreases MSC growth and osteogenic potentials, mechanical signals enhance MSC quantity and bias their differentiation toward osteoblastogenesis. Through a non-invasive dynamic hydraulic stimulation (DHS), we have found that DHS can mitigate trabecular bone loss in a functional disuse model via rat hindlimb suspension (HLS). To further elucidate the downstream cellular effect of DHS and its potential mechanism underlying the bone quality enhancement, a longitudinal in vivo study was designed to evaluate the MSC populations in response to DHS over 3, 7, 14, and 21 days. Five-month old female Sprague Dawley rats were divided into three groups for each time point: age-matched control, HLS, and HLS+DHS. DHS was delivered to the right mid-tibiae with a daily “10 min on-5 min off-10 min on” loading regime for five days/week. At each sacrifice time point, bone marrow MSCs of the stimulated and control tibiae were isolated through specific cell surface markers and quantified by flow cytometry analysis. A strong time-dependent manner of bone marrow MSC induction was observed in response to DHS, which peaked on day 14. After 21 days, this effect of DHS was diminished. This study indicates that the MSC pool is positively influenced by the mechanical signals driven by DHS. Coinciding with our previous findings of mitigation of disuse bone loss, DHS induced changes in MSC number may bias the differentiation of the MSC population towards osteoblastogenesis, thereby promoting bone formation under disuse conditions. This study provides insights into the mechanism of time-sensitive MSC induction in response to mechanical loading, and for the optimal design of osteoporosis treatments.

Higher plasma urate level is reported to be associated with a reduced risk and slower progression of Parkinson's disease (PD). In this study, we explored the effects of urate on dopaminergic neurons in nigrostriatal pathway in the 6-hydroxydopamine (6-OHDA) unilaterally lesioned rats. Uric acid (UA), when given twice daily at 200 mg/kg intraperitoneally for 10 consecutive days, elevated urate (the anionic form of UA) in plasma and striatum by 55% and 36.8%, respectively, as compared with vehicle group. This regimen of UA was found to ameliorate the behavioral deficits, dopaminergic neuron loss as well as dopamine depletion in the nigrostriatal system. Moreover, UA administration was capable of increasing glutathione level and superoxide dismutase activity while decreasing malondialdehyde accumulation in striatum. In addition, the phosphorylation of both protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3β) in the lesioned striata of 6-OHDA-lesioned rats was dramatically reduced as compared with sham-operated rats. This reduction was attenuated in the Parkinsonian rats receiving UA treatment. Similarly, in vitro findings showed that UA alleviated the decrease in Akt activation and the increase in GSK3β activity caused by 6-OHDA. Furthermore, neuroprotection by urate and its regulation on GSK3β phosphorylation at Ser9 was found to be abolished in the presence of PI3K inhibitor. Therefore, our findings demonstrated that urate was able to protect dopaminergic neurons in rat nigrostriatal pathway against the neurotoxicity of 6-OHDA, and showed that its beneficial effects may be related to its regulation on Akt/GSK3β signaling.

Bone fluid flow (BFF) has been demonstrated as a critical regulator in mechanotransductive signaling and bone adaptation. Intramedullary pressure (ImP) and matrix strain have been identified as potential generators to regulate BFF. To elevate in vivo oscillatory BFF using ImP, a dynamic hydraulic stimulation (DHS) approach was developed. The objective of this study was to evaluate the effects of DHS on mitigation of bone loss and structural alteration in a rat hindlimb suspension (HLS) functional disuse model. Sixty-one 5-month old female Sprague–Dawley rats were divided into five groups: 1) baseline control, 2) age-matched control, 3) HLS, 4) HLS + static loading, and 5) HLS + DHS. Hydraulic flow stimulation was carried out daily on a “10 min on–5 min off–10 min on” loading regime, 5 days/week, for a total of 4 weeks in the tibial region. The metaphyseal trabecular regions of the proximal tibiae were analyzed using μCT and histomorphometry. Four weeks of HLS resulted in a significant loss of trabecular bone, leading to structural deterioration. HLS with static loading alone was not sufficient to attenuate the bone loss. Bone quantity and microarchitecture were significantly improved by applying DHS loading, resulting increase of 83% in bone volume fraction, 25% in trabecular number and mitigation of 26% in trabecular separation compared to HLS control. Histomorphometry analysis on trabecular mineralization coincided with the μCT analysis, in which DHS loading yielded increases of 34% in histomorphometric BV/TV, 121% in MS/BS, 190% in BFR/BS and 146% in BFR/BV, compared to the HLS control. Overall, the data demonstrated that dynamic hydraulic flow loading has potentials to provide regulatory signals for mitigating bone loss induced by functional disuse. This approach may provide a new alternative mechanical intervention for future clinical treatment for osteoporosis.