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Stem cell-based therapeutic approach provides a possible treatment for critical limb ischemia (CLI) by inducing revascularization and regenerating ischemic tissue. However, the clinical benefit is modest due to low cell survival and limited efficacy after transplantation. Cardiac-derived stem cells (CSCs) might be a novel cell source for CLI treatment owing to their superb endothelial differentiation potential and angiogenic paracrine functions. In this study, the angiogenic ability of CSCs was maximized by genetic engineering with constitutively active form of hypoxia-inducible factor-1α (CA-HIF-1α), resistant to oxygen-dependent degradation. CSCs transfected with CA-HIF-1α (CA-HIF-CSCs) promoted supplementary expression of proangiogenic factors including VEGF, bFGF, Ang-1 and PDGF-B, along with enhanced angiogenic function including migratory effect, tube formation and endothelial differentiation potential. In the mouse CLI model, CA-HIF-CSCs transplanted into the ischemic region using fibrin gel as cell delivery vehicle, improved blood perfusion and limb functional recovery with minimal incidence of foot necrosis and limb loss by promoting new vessel formation. Histological evidence further confirmed that CA-HIF-CSC/gel treatment markedly alleviated muscle degeneration and fibrosis. CSCs genetically engineered with constitutively active HIF-1α provide a novel therapeutic modality in CLI combining stem cell and gene therapy.

Epidemiological studies demonstrate that men with periodontitis are also susceptible to benign prostatic hyperplasia (BPH) and that periodontal treatment can improve the prostatic symptom. However, molecular links of this relationship are largely unknown. The goal of the current study was to elucidate the effects of experimental periodontitis on the hyperplasia of prostate and whether oxidative stress and inflammation participated in this process. For this purpose, ligature-induced periodontitis, testosterone-induced BPH, and the composite models in rats were established. Four weeks later, all the rats were sacrificed and the following items were measured: alveolar bone loss and histological examination of periodontal tissues were taken to assess the establishment of periodontitis model, prostate index and histological examination of prostate tissues were taken to test the establishment of the BPH model, inflammatory cytokines in plasma were assessed, and Bax/Bcl-2 proteins related to cell apoptosis were analyzed via western blot analysis. To further investigate whether oxidative stress participates in the aggravation of BPH, in vitro models were also conducted to measure the production of intracellular reactive oxygen species (ROS) and hydrogen peroxide (H2O2) concentration. We found that simultaneous periodontitis and BPH synergistically aggravated prostate histological changes, significantly increased Ki67 proliferation, and reduced apoptosis in rat prostate tissues. Also, our results showed that periodontal ligation induced increased Bcl-2 protein expression, whereas Bax expression was decreased in BPH rats than in normal rats. Compared with the control group, periodontitis and BPH both significantly enhanced inflammatory cytokine levels of TNF-α, IL-6, IL-1β, and CRP. Furthermore, Porphyromonas gingivalis lipopolysaccharide induced enhanced generation of intracellular expression of ROS and H2O2 in BPH-1 cells. Our experimental evidence demonstrated that periodontitis might promote BPH development through regulation of oxidative stress and inflammatory process, thus providing new strategies for prevention and treatment of BPH.

Background The lower limb joints, including hip and knee, are the most commonly involved joints in haemophilic arthropathy. With a higher risk of transfusion, total hip and knee arthroplasty (THA and TKA) are still the first choice after failure of conservative treatment. In the present study, we aimed to analyze clinical outcomes and complications rate after total joint arthroplasty of the lower limbs using tranexamic acid (TXA) or not. Methods Thirty-four patients with haemophilia A undergoing 24 TKA and 18 THA were evaluated in this retrospective study (No. 201302009). Based on using TXA or not, they were divided into either TXA (12 knees and 10 hips) or Non-TXA groups (12 knees and 8 hips). Total blood loss, intraoperative blood loss, total amount of FVIII usage, range of motion, inflammatory biomarkers, joint function, pain status, complication rate and patient satisfaction were assessed and compared at a mean follow-up of 68 months. Results Usage of TXA can decrease not only the perioperative blood loss (p = 0.001), transfusion rate (p = 0.017) and supplemental amount of FVIII (p

Background We designed the current study to understand the normal trajectories of interleukin-6 (IL-6) and C-reactive protein (CRP) in the immediate hours and days after primary total knee arthroplasty (TKA) under the management of an enhanced recovery after surgery (ERAS) protocol and examined whether one or the other returned to normal more quickly. Methods In this prospective cross-sectional study, we examined the plasma IL-6 and CRP levels in 100 patients undergoing primary TKA at the following time points: 12 h preoperatively as well as postoperatively 12 h, 48 h, 3 days and 2 weeks. Patients were followed up for 1 year to monitor the postoperative complications, especially the infection. Results IL-6 peaked at 48 h postoperatively. Then IL-6 started to decline at 3 days postoperatively and went back to baseline level at 2 weeks (p = 0.950). CRP peaked at 3 days postoperatively. At 2 weeks, CRP declined to a normal range, without being significantly different from the baseline level (p = 0.816). Conclusion We found that under the ERAS scenario, the postoperative peak of IL-6 and CRP was deferred compared with previous studies. Compared to IL-6, CRP showed a gradual rise after surgery. Both of these two biomarkers returned to normal under the ERAS scenario. Future multiple-center studies with larger sample size can help define the thresholds of IL-6 and CRP for periprosthetic joint infection (PJI) early diagnosis. With these reference data, a clinician can make a quicker decision to perform aspiration to diagnose early PJI and benefits more patients.

AimsTo explore clinical features and outcome of 2019 novel coronavirus(2019-nCoV)-infected patients with high BNP levelsMethods and resultsData were collected from patients’ medical records, and we defined high BNP according to the plasma BNP was above > 100 pg/mL. In total,34 patients with corona virus disease 2019(COVID-19)were included in the analysis. Ten patients had high plasma BNP level. The median age for these patients was 60.5 years(interquartile range, 40-80y), and 6/10 (60%) were men. Underlying comorbidities in some patients were coronary heart disease (n=2, 20%), hypertesion (n=3,30%), heart failure (n=1,10%)and diabetes (n=2, 20%). Six (60%) patients had a history of Wuhan exposure. The most common symptoms at illness onset in patients were fever (n=7, 70%), cough (n=3, 30%), headache or fatigue(n=4,40%). These patients had higher aspartate aminotransferase(AST), troponin I, C reactive protein and lower hemoglobin, and platelet count,compared with patients with normal BNP, respectively. Compared with patients with normal BNP, patients with high BNP were more likely to develop severe pneumonia, and receive tracheal cannula, invasive mechanical ventilation, continuous renal replacement therapy, extracorporeal membrane oxygenation, and be admitted to the intensive care unit. One patient with high BNP died during the study.ConclusionHigh BNP is a common condition among patients infected with 2019-nCoV. Patients with high BNP showed poor clinical outcomes

AimsTo explore the epidemiological and clinical features of 2019 novel coronavirus(2019-nCoV)-infected patients with cardiac injury.Methods and resultsData were collected from patients’ medical records, and we defined cardiac injury according to cardiac biomarker troponin I level > 0.03 μg/L. Among the 291 patients, 15 (5.2%) showed evidence of cardiac injury. Of 15 hospitalized patients with cardiac injury, the median age was 65 years, and 11/15 (73.3%) were men. Underlying cardiovascular diseases in some patients were hypertension (n=7, 46.7%), coronary heart disease (n=3, 20%) and diabetes (n=3, 20%). The most common symptoms at illness onset in patients with cardiac injury were fever (n=11, 73.3%), cough (n=7, 46.7%), headache or fatigue (n=5, 33.3%) and dyspnea (n=4, 26.7%). These patients had higher systolic pressures, white blood cell count, neutrophil count, troponin I, brain natriuretic peptide, D-dimer and lower lymphocyte count, and platelet count, compared with patients without cardiac injury, respectively. Bilateral infiltrates on chest X-ray and elevated C-reactive protein occurred in all patients with cardiac injury. Compared with patients without cardiac injury, patients with cardiac injury were more likely to develop acute respiratory distress syndrome, and receive mechanical ventilation, continuous renal replacement therapy, extracorporeal membrane oxygenation and vasopressor therapy and be admitted to the intensive care unit.ConclusionCardiac injury is a common condition among patients infected with 2019-nCoV. Compared with patients without cardiac injury, the clinical outcomes of patients with cardiac injury are relatively worse.

In this paper, carboxylated C3N4 (g-C3N4-COOH) was prepared by a new method, and then combined with ZnSe quantum dots (QDs) through amide reaction to form g-C3N4-COOH/ZnSe nanocomposite and used for detecting kanamycin. The prepared g-C3N4-COOH/ZnSe nanocomposite was used as the subatrate of aptasensor. Then, the g-C3N4-COOH/ZnSe nanocomposite-modified electrode was incubated with aptamer DNA (NH2-DNA), after cholamine blocked the unbond sites of the electrode surface, the ferrocene-labled quenching probe (Fc-DNA) as electrochemiluminescence (ECL) signal quencher was incubated on the electrode surface through base complementation with aptamer DNA. In the absence of kanamycin, the ECL signal was quenched effectively by Fc-DNA. On the contrary, kanamycin was specifically bond with aptamer DNA, and Fc-DNA was detached from the aptasensor electrode surface because of the deformation of aptamer DNA, generating an effectively enhanced ECL signal. The aptasensor exhibited a wide detection range for detecting kanamycin (1.0 nM − 100 μM) with a low limit of detection (0.7982 nM). The prepared aptasensor displayed a stable and selective detection for kanamycin, and also provided a promising strategy for a variety of other protein target.

Critical limb ischemia (CLI) is the most advanced stage of peripheral artery disease, associated with significant risk of limb loss, morbidity and mortality; however, there remains unmet therapeutic needs for arterial revascularization and ischemic tissue repair. Stem cell therapies have emerged as compelling candidates due to beneficial proangiogenic and immunosuppressive function. Nevertheless, in vivo efficacy was insufficient in proliferation, differentiation and survival/engraftment rate. Cardiac stem cells (CSCs) was firstly attempted for CLI as a novel therapeutic modality to provide superior angiogenic potency to bone marrow-derived stem cells (BMSCs). It was noted that CSCs demonstrated 3.2-fold in HGF, 2.9-fold in VEGF and 8.7-fold in PDGF-B higher gene expressions compared to BMSCs. To enhance the hypoxia-induced proangiogenic effect, CSCs were transfected with hypoxia-inducible factor-1 alpha (HIF-1α) by using electroporation method, specifically optimized for CSCs yielding 45.77% of transfection efficiency and 89.75% of viability. HIF-1α overexpression significantly increased CSC survival in hypoxia, proangiogenic factors production and endothelial differentiation. In mouse hind limb ischemia model, local intramuscular delivery of CSC overexpressing HIF-1α (HIF-CSC) significantly improved the blood flow recovery. Histological analysis revealed that muscle degeneration and fibrosis in the ischemic limb were attenuated. Local delivery of HIF-CSC might be a promising option for ischemic tissue restoration.

Pyroptosis is a type of programmed cell death, which has been associated with multiple inflammatory diseases including diabetic atherosclerosis (DA). This study aims to explore the role of sinapic acid (SA) in the pyroptosis of macrophages in DA. Our results from the in vivo experiments showed that low-dose (≤50 mg/kg) chronic SA administration suppressed serum endothelin 1 (ET-1) and interleukin-1β (IL-1β) contents, pyroptotic death of bone marrow-derived macrophages, and the expression of pyroptotic proteins ASC, NRLP3, and caspase-1. Besides, lncRNA-metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was robustly upregulated in the macrophages of rats with DA and could be lowered by low-dose SA administration. Gene overexpression and knockdown experiments showed that MALAT1 had a modestly positive effect on the pyroptosis of normal macrophages. Moreover, in macrophages incubated with high-glucose and Ox-LDL, 1-μM SA treatment displayed a suppressive effect on the cell pyroptosis similar to that of MALAT1 knockdown. Transfection of the pcDNA-MALAT1 expression vector counteracted the decrease in MALAT1 expression and macrophage pyroptosis caused by SA. In conclusion, low-dose SA can abate the pyroptosis of macrophages by downregulation of lncRNA-MALAT1 in rats with DA.

Immune checkpoint therapy encounters significant challenges in clinic, including low response rate, acquired resistance and immune-related adverse events. Combination immunotherapy targeting multiple independent but complementary pathways in immune evasion has the potential to enhance therapeutic efficacy. Herein, a combination therapeutic strategy that dually inhibiting FGL1, a recently discovered main ligand for immune checkpoint LAG-3, and TGF-β1, an immunosuppressive cytokine, is firstly reported for colorectal cancer immunotherapy by blocking immune checkpoint and modulating tumor microenvironment simultaneously. We established a cRGD-modified exosome with high siFGL1 and siTGF-β1 loading efficiency (cRGD-Exo/siMix) to realize the co-silence of FGL1 and TGF-β1. The constructed cRGD-Exo/siMix showed a significant anti-tumor effect both in vitro and in vivo. Analysis of the tumor immune microenvironment demonstrated an increased number of tumor infiltration CD8+ T cells while a decreased number of immunosuppressive cells, implying that this therapeutic approach boosted anti-tumor immunity by reshaping the tumor microenvironment. This work provides a new strategy for siRNA delivery and its applications in combined cancer immunotherapy.

Objective To evaluate contextual effects in the form of placebo responses (PRs) for patient-reported pain and function and objectively measured function in osteoarthritis (OA) clinical trials. Methods Two authors independently searched major electronic databases from inception to 20 May 2019. Included studies were randomized, placebo-controlled OA trials of pharmacological agents reporting both patient-reported and objectively measured outcomes. PRs for each type of outcome measure were compared by standardized mean differences (SMDs). The placebo response ratio (PRR) assessed the placebo to treatment effect size. The effect sizes of PRs and PRRs were pooled using a random effects model. Results Twenty-one trials met the inclusion criteria; 20 were double-blinded with one not reporting on blinding status. Compared with patients’ self-reported outcome (PRO) pain, PRs were significantly lower for PRO function (SMD − 0.16 [95% CI = − 0.28, − 0.05], p = 0.006), objectively measured muscle strength (SMD − 0.34 [95% CI − 0.58, − 0.10], p = 0.006), and range of motion (SMD = − 0.31 [95% CI = − 0.54, − 0.08], p = 0.008) function. Generally, PRs for function outcomes (patient-reported and objectively measured) were similar. The overall PRR for different measures ranged from the smallest (most favorable) for walking time/distance (0.30, 95% CI 0.16 to 0.43) to the largest for PRO pain (0.44, 95% CI 0.23 to 0.65). Conclusion Function measures both subjective and objective had less contextual effects than pain measures in OA trials. Our results support the OMERACT-OARSI recommendations to include measures of physical function in all clinical trials of hip and knee OA and suggest that a greater use of function measures might enhance the success rates of pharmacological OA trials. Increasing the availability of mobile health apps should facilitate the acquisition of measured function data. Electronic supplementary material The online version of this article (10.1186/s13075-019-1951-6) contains supplementary material, which is available to authorized users.

The proliferation and migration of vascular smooth muscle cells (VSMCs) play crucial roles in the pathogenesis of diabetes and its complications. Thymoquinone (TQ) is the primary bioactive component of Nigella sativa L. seed oil, which exhibits antihyperglycemic effect in diabetic rats, but its role in VSMC proliferation and migration has not been investigated. The results of MTT assay and flow cytometry assay indicated that TQ dose-dependently inhibited angiotensin II (Ang II)-induced VSMCs' cell cycle progression, as well as cyclin D1 expression, whereas p21 expression was altered conversely. TQ dose-dependently suppressed Ang II-induced VSMC migration accompanied by reduced MMP-9 expression. In addition, we observed the elevated reactive oxygen species (ROS) generation and NADPH oxidase activity and reduced superoxide dismutase activity in Ang II-treated VSMCs, which were dose-dependently reversed by TQ. Western blot analysis indicated that TQ dose-dependently restored Ang II-inhibited expression of p-AMPK, PPARγ, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) proteins. Furthermore, adenosine monophosphate-activated protein kinase (AMPK) inhibitor Compound C and PGC-1α siRNA transfection abrogated the activation of TQ on Ang II-inhibited AMPK/PPARγ/PGC-1α signaling, but abolished the inhibitory effects of TQ on Ang II-induced VSMC proliferation and migration, as well as ROS generation. Taken together, these results demonstrated that TQ inhibited Ang II-induced VSMC proliferation and migration through the AMPK/PPARγ/PGC-1α pathway.

A primary obstacle to an HIV-1 cure is long-lived viral reservoirs, which must be eliminated or greatly reduced. Cure strategies have largely focused on monitoring changes in T cell reservoirs in peripheral blood (PB), even though the lymphoid tissues (LT) are primary sites for viral persistence. To track and discriminate viral reservoirs within tissue compartments we developed a specific and sensitive next-generation in situ hybridization approach to detect vRNA, including vRNA+ cells and viral particles (“RNAscope”), vDNA+ cells (“DNAscope”) and combined vRNA and vDNA with immunohistochemistry to detect and phenotype active and latently infected cells in the same tissue section. RNAscope is highly sensitive with greater speed of analysis compared to traditional in situ hybridization. Highly sensitive and specific DNAscope detected SIV/HIV vDNA+ cells, including duplexed detection of vDNA and vRNA or immunophenotypic markers in the same section. Analysis of LT samples from macaques prior to and during combination antiretroviral therapy demonstrated that B cell follicles are an important anatomical compartment for both latent and active viral persistence during treatment. These new tools should allow new insights into viral reservoir biology and evaluation of cure strategies.

Non-injectable delivery of peptides and proteins is not feasible due to the limitations of large molecular mass, high hydrophilic properties, and gastrointestinal degradation. Therefore, proposing a new method to solve this problem is a burning issue. The objective of this study was to propose a novel protein delivery strategy to overcome the poor efficacy and irritation of buccal insulin delivery. In this study, we applied a conjugate of cell-penetrating peptides (LMWP) and insulin (INS-PEG-LMWP) for buccal delivery. INS-PEG-LMWP was prepared using insulin solution and mixture as references. The transport behaviour, in vivo bioactivity, hypoglycaemic effect, and safety of INS-PEG-LMWP were systematically characterised. An in vitro study demonstrated that the uptake and transportation of INS-PEG-LMWP across buccal mucosal multilayers significantly increased. By comparing the effects of different endocytic inhibitors on INS-PEG-LMWP uptake, the conjugate might be delivered via an energy independent, electrostatically adsorbed pathway. INS-PEG-LMWP's relative pharmacological bioavailability was high and its relative bioavailability was up to 26.86%, demonstrating no visible mucosal irritation. Cell-penetrating peptides are likely to become a reliable and safe tool for overcoming insulin's low permeability through the epithelial multilayers, the major barrier to buccal delivery.

Human gammaherpesviruses are associated with malignancies in HIV infected individuals; in macaques used in non-human primate models of HIV infection, gammaherpesvirus infections also occur. Limited data on prevalence and tumorigenicity of macaque gammaherpesviruses, mostly cross-sectional analyses of small series, are available. We comprehensively examine all three-rhesus macaque gammaherpesviruses -Rhesus rhadinovirus (RRV), Rhesus Lymphocryptovirus (RLCV) and Retroperitoneal Fibromatosis Herpesvirus (RFHV) in macaques experimentally infected with Simian Immunodeficiency Virus or Simian Human Immunodeficiency Virus (SIV/SHIV) in studies spanning 15 years at the AIDS and Cancer Virus Program of the Frederick National Laboratory for Cancer Research. We evaluated 18 animals with malignancies (16 lymphomas, one fibrosarcoma and one carcinoma) and 32 controls. We developed real time quantitative PCR assays for each gammaherpesvirus DNA viral load (VL) in malignant and non-tumor tissues; we also characterized the tumors using immunohistochemistry and in situ hybridization. Furthermore, we retrospectively quantified gammaherpesvirus DNA VL and SIV/SHIV RNA VL in longitudinally-collected PBMCs and plasma, respectively. One or more gammaherpesviruses were detected in 17 tumors; generally, one was predominant, and the relevant DNA VL in the tumor was very high compared to surrounding tissues. RLCV was predominant in tumors resembling diffuse large B cell lymphomas; in a Burkitt-like lymphoma, RRV was predominant; and in the fibrosarcoma, RFHV was predominant. Median RRV and RLCV PBMC DNA VL were significantly higher in cases than controls; SIV/SHIV VL and RLCV VL were independently associated with cancer. Local regressions showed that longitudinal VL patterns in cases and controls, from SIV infection to necropsy, differed for each gammaherpesvirus: while RFHV VL increased only slightly in all animals, RLCV and RRV VL increased significantly and continued to increase steeply in cases; in controls, VL flattened. In conclusion, the data suggest that gammaherpesviruses may play a significant role in tumorogenesis in macaques infected with immunodeficiency viruses., Author summary Human gammaherpesviruses cause malignancies in HIV infected persons; in SIV infected macaques, gammaherpesvirus infections also occur. To understand the potential role of the rhesus gammaherpesviruses, RRV, RFHV and RLCV in cancers occurring in monkeys during SIV and SHIV studies spanning the last 15 years, we developed assays to measure the DNA viral load (VL) of each virus in these tumors and unaffected macaque tissues. We further characterized the tumors using immunohistochemistry and in situ hybridization, and quantified gammaherpesvirus DNA VL in PBMCs collected longitudinally during the original studies. We examined 18 animals with tumors and 32 controls. In all tumors, we detected one or more gammaherpesviruses; generally, one virus was predominant and very abundant compared to surrounding non-tumor tissues. SIV RNA VL in plasma and RLCV VL in PBMCs were independently associated with cancer risk. The longitudinal patterns of gammaherpesviruses VL, from SIV infection to death differed in cases and controls: while RFHV VL increased only slightly in all animals, RLCV VL and RRV VL increased significantly and continued to increase in cases, but flattened in controls. These data suggest that gammaherpesviruses may play a significant role in tumorogenesis in macaques infected with immunodeficiency viruses.

Disruption of the mucosal epithelium during lentivirus infections permits translocation of microbial products into circulation, causing immune activation and driving disease. Although the liver directly filters blood from the intestine and is the first line of defense against gut-derived antigens, the effects of microbial products on the liver are unclear. In livers of normal macaques, minute levels of bacterial products were detectable, but increased 20-fold in simian immunodeficiency virus (SIV)–infected animals. Increased microbial products in the liver induced production of the chemoattractant CXCL16 by myeloid dendritic cells (mDCs), causing subsequent recruitment of hypercytotoxic natural killer (NK) cells expressing the CXCL16 receptor, CXCR6. Microbial accumulation, mDC activation, and cytotoxic NK cell frequencies were significantly correlated with markers of liver damage, and SIV-infected animals consistently had evidence of hepatitis and fibrosis. Collectively, these data indicate that SIV-associated accumulation of microbial products in the liver initiates a cascade of innate immune activation, resulting in liver damage.

Objective To investigate the effect of acetabular component orientation on the basic stress path above the acetabular dome in the recommended safe zone. Methods A subject-specific normal hip finite element model was generated and a convergence study carried out to determine the number of material properties for trabecular bone using a normal hip model. Four abduction angles (35°, 40°, 45° and 50°) and four anteversion angles (10°, 15°, 20° and 25°) from the recommended safe zone of acetabular cup orientation were chosen to simulate acetabular reconstruction. The distribution and level of periacetabular stress was assessed using a normal hip model as a control and 16 reconstructed acetabula in simulated single-legged stances. Results The error of the average stress between plans four and five (50 and 100 materials for trabecular bone respectively) was 4.8%, which is less than the previously defined 5% error. The effect of acetabular component orientation on stress distribution in trabecular bone was not pronounced. When the acetabular component was at 15° anteversion and the abduction angle was 40° or 45°, the stress level on posterolateral cortical bone above the acetabular dome was as stable as that in the normal hip model. Conclusions Acetabular component orientation affects the basic stress path above the acetabular dome. Thus, orientation should be considered when attempting to restore normal biomechanics in the main load-bearing area.

It is still controversial on the optimal timing of tourniquet used in total knee arthroplasty (TKA). Most previous studies focused on the comparison of different tourniquet application in controversial TKA, while the aim of our work was to compare three strategies of tourniquet application in minimally invasive TKA. 90 patients were enrolled in this study. Based on the different tourniquet application strategies, they were divided into three groups. Group A: using tourniquet during the whole surgery; Group B: tourniquet inflated before incision and deflated after the hardening of the cement; Group C: using tourniquet during the cementation. Blood loss and serum levels of C-reactive protein, IL-6, creatine kinase and myoglobin were checked preoperatively. The HSS knee score, VAS pain score, range of motion (ROM), limb swelling and hospital stays were also recorded. The mean levels of Hb and Hct were lower in Group C (104.2 ± 10.4 g/L, 31.8 ± 3.2 %) than those in Groups A (111.4 ± 14.4 g/L, p = 0.035; 34.1 ± 4.1 %, p = 0.032) and B (112.8 ± 14.3 g/L, p = 0.013; 34.5 ± 3.7 %, p = 0.011) immediately after the surgery. Compared with Groups A and B, both serum inflammation and muscle damage markers were lower in Group C. There were no significant differences between the groups in terms of HSS knee score, ROM, estimated blood loss, swelling ratio, VAS pain score and hospital stays. Using a tourniquet full time in minimally invasive TKA causes less intraoperative blood loss and more excessive inflammation and muscle damage. However, the advantage of part-time using tourniquet did not show in early functional outcomes.

Early after HIV infection there is substantial depletion of CD4+ T cells in the gastrointestinal (GI) tract lamina propria (LP), with associated epithelial barrier damage, leading to microbial translocation and systemic inflammation and immune activation. In this study, we analyzed these early events in the GI tract in a cohort of Thai acute HIV-infected patients and determined the effect of early combination antiretroviral treatment (cART). HIV-uninfected and chronically and acutely HIV-infected patients at different Fiebig stages (I–V) underwent colonic biopsies and then received cART. Immunohistochemistry and quantitative image analysis were performed on cross-sectional and longitudinal colon biopsy specimens (day 0 to week 96) to measure GI tract damage (infiltration of polymorphonuclear cells), inflammation (Mx1, TNF-α), immune activation (Ki-67), and the CD4+ T cell population in the LP. The magnitude of GI tract damage, immune activation, and inflammation was significantly increased, with significantly depleted CD4+ T cells in the LP in all acutely infected groups prior to cART compared with HIV-uninfected control participants. While most patients treated during acute infection resolved GI tract inflammation and immune activation back to baseline levels after 24 weeks of cART, most acutely infected participants did not restore their CD4+ T cells after 96 weeks of cART.

(See the editorial commentary by Michael on pages 875–6.) Persistent immune activation is a hallmark of human immunodeficiency virus type 1 (HIV-1) infection in humans and simian immunodeficiency virus (SIV) infection in rhesus macaques. In progressive HIV/SIV infections, the level of immune activation has been demonstrated to be a stronger predictor of disease progression than either plasma viral load or peripheral CD4+ T-cell count [1, 2]. Acute infection is associated with the development of intense immune activation that remains abnormally high throughout the course of infection in the absence of antiretroviral treatment (ART). This persistent pathological immune activation is associated with elevated proinflammatory cytokine and coagulation markers that correlate with an increased risk of death among HIV-positive patients [3]. In SIV-infected monkeys and HIV-infected humans, early augmentation of proinflammatory cytokines and chemokines in lymphoid tissues may play a key role in modulating disease progression [4, 5]. Notably, early high expression of both proinflammatory and antiinflammatory molecules in lymphoid tissues has been proposed to contribute to enhanced immune activation, resulting in tissue damage rather than viral control, thus driving disease progression [4, 6]. Dissecting the elements of the acute inflammatory response that lead to chronic immune activation and disease progression may provide insights that can aid the development of specific adjunctive therapies that may limit inflammation-induced tissue damage and thereby improve the prognosis of HIV-infected individuals. The inflammatory response to infections reflects the aggregate effects of various cytokines and other soluble factors produced by multiple cellular populations. Tumor necrosis factor (TNF) has been identified as a key regulator and amplifier of inflammatory responses, with effects on the innate and adaptive immune systems [7–9]. TNF has been proposed to contribute to the overall pathogenesis of HIV/SIV infection, enhancing viral propagation, lymphocyte depletion, and clinical manifestations of disease. High TNF levels have been shown to be associated with all stages of HIV-1 infection, with increased TNF expression in the plasma and lymphoid tissues during acute HIV-1 infection [10, 11]. Sequential plasma samples collected during the eclipse and exponential viral expansion phases of acute HIV-1 infection demonstrated rapid and robust inflammatory responses, including early and sustained increases in TNF, that likely have immunopathological consequences by promoting immune activation, viral replication, and CD4+ T-cell loss [12]. In nonhuman-primate models, elevated TNF expression has been shown in the serum, peripheral blood mononuclear cells, lymph nodes, and brain of infected animals in temporal association with SIV replication during acute infection [13–15]. In contrast, studies of nonprogressive and apathogenic SIV infection in natural hosts of SIV have shown a lack of TNF upregulation throughout the acute and chronic stages of SIV infection [16], suggesting that differences in the host acute inflammatory response may be critically important in pathogenesis and disease progression. Since TNF inhibitors are used to treat a range of inflammatory conditions [17, 18], and given the data suggesting that TNF may play a key role in the acute inflammatory response to HIV/SIV infection, we evaluated the effect of anti-TNF antibody (adalimumab; Humira) treatment during the first 12 weeks of SIV infection in a small, nonhuman-primate study. While treatment did not affect viral replication dynamics or systemic T-cell activation profiles, inhibition of the biological activity of TNF reduced proinflammatory gene expression in lymphoid tissues during acute infection and attenuated antiinflammatory responses to SIV associated with pathological damage of lymphoid tissues [6]. Specifically, TNF blockade attenuated 3 manifestations of inflammation associated with SIV infection: (1) infiltration of CD163+ macrophages and neutrophils into the paracortical T-cell zone, (2) transforming growth factor β (TGF-β) expression in the T-cell zone, and (3) lymphoid tissue fibrosis, which was associated with less CD4+ T-cell loss, demonstrating that modulation of inflammatory responses to HIV/SIV infection may beneficially affect pathogenesis, independent of any direct effects on viral replication.

CD4+ T cells play a central role in the immunopathogenesis of HIV/AIDS, and their depletion during chronic HIV infection is a hallmark of disease progression. However, the relative contribution of CD4+ T cells as mediators of antiviral immune responses and targets for virus replication is still unclear. Here, we have generated data in SIV-infected rhesus macaques (RMs) that suggest that CD4+ T cells are essential in establishing control of virus replication during acute infection. To directly assess the role of CD4+ T cells during primary SIV infection, we in vivo depleted these cells from RMs prior to infecting the primates with a pathogenic strain of SIV. Compared with undepleted animals, CD4+ lymphocyte-depleted RMs showed a similar peak of viremia, but did not manifest any post-peak decline of virus replication despite CD8+ T cell- and B cell-mediated SIV-specific immune responses comparable to those observed in control animals. Interestingly, depleted animals displayed rapid disease progression, which was associated with increased virus replication in non-T cells as well as the emergence of CD4-independent SIV-envelopes. Our results suggest that the antiviral CD4+ T cell response may play an important role in limiting SIV replication, which has implications for the design of HIV vaccines.

The objective of this study is to develop a finite element analysis model that simulates the temperature profile in concrete-filled steel tubular structures during welding procedure in which several metal plates are fixed on the outer surface of steel tube to increase the strength and stiffness of it. In the present model, the thermal property such as thermal conductivity of the steel phase is assumed to be functions of temperature variable. Spatial and temporal distributions of temperature are illustrated under extreme weld heating conditions to investigate the behaviors of the structure at every time step. Simulation results indicate that the maximum value of temperature on the interface of steel and concrete caused by the weld heat source doesn’t damage the mechanical properties of concrete and steel.

In this paper, novel filled materials EPS-blocks of cast-in-situ slabs are presented. And EPS-blocks with light weight which are inexpensive are validated to be sufficient strong as filled materials to bring an innovation for the development of cast-in-situ slabs. Based on modal analysis, it is found that the decreased weight has a greater influence to the mode of the slab than the weakened stiffness. According to harmonic response analysis, tensile stress distributions of the slab with EPS-blocks are depicted in figures and explained. Typically, orifice stress distributions are expounded and stress variations of nodes in different places are illustrated. From these studies, it is concluded that the steady state dynamic performance of the slab with EPS-blocks is good.

This study is to compare the therapeutic effect of posterior lumbar interbody fusion (PLIF) and transforaminal lumbar interbody fusion (TLIF) with pedicle screw fixation on treatment in adult degenerative spondylolisthesis. A retrospective analysis of 187 patients to compare the complications and associated predictive factors of the two techniques of one level lumbar fusion. Ninety-one had PLIF with two cages and pedicle fixation (group 1), and ninety-six had TLIF with one cage and pedicle fixation (group 2). The two groups had similar age and sex distribution, and level of pain. Inclusion criteria and outcome measurements were identical in both groups. The two groups were operated on with autograft and cage with pedicle fixation. Before surgery and at the 2-year follow-up, pain (VAS) and functional disability (JOA) were quantified. The results showed there were no intraoperative deaths in our study. In the end 176 cases had 2-year follow-up while 11 cases were lost to follow-up. The follow-up rate was 93.4% (85/91) in the PLIF group and 94.8% (91/96) in the TLIF group. All patients had bone fusion, and there were no cases of cage extrusion. The pain index improved from 7.08 +/- 1.13 to 2.84 +/- 0.89 in PLIF patients and improved from 7.18 +/- 1.09 to 2.84 +/- 0.91 in TLIF patients (P0.001). There were 42 cases of excellent, 29 cases of good, 11 cases of general, and 3 cases of poor results in PLIF group. There were 46 cases of excellent, 31 case of good, 12 case of general, and 2 cases of poor results in TLIF group. The JOA score in all patients was 84.1% of good or excellent (83.5% in PLIF and 84.6% in TLIF, P0.05). The average preoperative slip was 30.1 +/- 7.2% in PLIF group while in the TLIF it was 31.4 +/- 8.3%. Immediately post operatively it was reduced to 7.3 +/- 2.1% and 7.4 +/- 2.7% and at last F/U it was 8.1 +/- 2.8% and 8.2 +/- 2.6%, respectively. The average of reduction rate was 75.2 +/- 6.4% in PLIF and 75.4 +/- 6.2 in TLIF on the initial post operatively X-ray, and 72.6 +/- 5.2% and 72.4 +/- 5.4% on the follow-up. The percentage rate, reduction rate and lost of reduction rate between the two groups was similar (P0.05). The average pre operative disk and foramen height in the PLIF group improved from 6.8 +/- 2.3 and 14.2 +/- 1.7 preoperatively to 11.6 +/- 1.5 and 18.7 +/- 1.8 post operatively, respectively. At last follow up there was minimal lost of correction down to 11.24 +/- 1.2 and 18.1 +/- 1.8, respectively. Similarly in the TLIF group, pre operative disk and foramen height were improved from 6.7 +/- 1.7 and 14.1 +/- 1.8 to 11.4 +/- 1.6 and 18.5 +/- 1.6 immediately post operative. At last follow up minimal lost of correction was noted with average disc height of 11.3 +/- 1.4 and 18.2 +/- 1.7. Both techniques achieve statistical significance in restoration of disc and foraminal (P0.01); however, there was no statistical difference between the two techniques. In conclusion, interbody fusion with either a PLIF technique or a TLIF technique provides good outcomes in the treatment of adult degenerative spondylolisthesis. The TLIF procedure is simpler and is as safe and effective as the PLIF technique.

Mucosal damage to the gastrointestinal (GI) tract with resulting microbial translocation is hypothesized to significantly contribute to the heightened and persistent chronic inflammation and immune activation characteristic to HIV infection. Here we employ a non-human primate model of chemically induced colitis in SIV-uninfected rhesus macaques that we developed using dextran sulfate sodium (DSS), to directly test this hypothesis. DSS treatment results in GI barrier damage with associated microbial translocation, inflammation and immune activation. The progression and severity of colitis are longitudinally monitored by a magnetic resonance imaging approach. DSS treatment of SIV-infected African green monkeys, a natural host species for SIV that does not manifest GI tract damage or chronic immune activation during infection, results in colitis with elevated levels of plasma SIV RNA, sCD14, LPS, CRP and mucosal CD4+ T-cell loss. Together these results support the hypothesis that GI tract damage leading to local and systemic microbial translocation, and associated immune activation, are important determinants of AIDS pathogenesis., HIV-1 infection in humans and SIV infection in rhesus macaques are associated with mucosal damage to the gastrointestinal tract, microbial translocation and chronic immune activation. Here the authors develop a non-human primate DSS colitis model that recapitulates these aspects of the disease in uninfected rhesus macaques.

Nitric oxide has important effects on bone cell function. To verify that nitric oxide can protect against bone loss associated with estrogen deficiency, which is dependent on different concentrations of nitric oxide, we applied different doses of nitric oxide to ovariectomized rats. Fifty 12-week-old Sprague-Dawley female rats had ovariectomies, and 10 rats had sham operations. The ovariectomized rats were randomized into five groups: ovariectomized only; 17-beta-estradiol; low-dose nitroglycerin; middle-dose nitroglycerin; and high-dose nitroglycerin. After 12 weeks, the bone mineral density, dry weight, ash weight, calcium content, and nitric oxide concentration were determined. Compared with these same measurements in the sham-operated group, the bone mineral density, dry weight, ash weight, calcium content, and nitric oxide concentration decreased in the control group. Treatment with low-dose nitroglycerin, middle-dose nitroglycerin, and 17-beta-estradiol maintained bone mineral density and reversed the effects of ovariectomy on dry weight, ash weight and calcium content when compared with those in the control group. There were no differences in the bone mineral density, dry weight, ash weight, or calcium concentration between the ovariectomized-only rats and the rats treated with high-dose nitroglycerin. Results of this study suggest that nitric oxide treatment can counteract bone loss in ovariectomized rats. Furthermore, supplementation with a similar or slightly greater than physiologic concentration of nitric oxide has a potentially positive impact on osteoporosis.

We study the effect of noise on a nonlinear neurodynamical model for disease states of recurrent affective disorders. Specifically, we consider how noise affects a model state with periodic event generation close to period-doubling bifurcations. Our simulations demonstrate noisy precursors of the bifurcations. The precursors can be seen in the return maps of the time series and can be quantified with a recently developed algorithm for the detection of unstable periodic orbits. Implications for the neurobiology and course of mood disorders are discussed.

Pediatric septic shock is a major health problem in the United States, with 42,000 cases annually and an approximate 10% mortality rate. Studies have shown that pediatric septic shock patients regularly have critically low levels of serum zinc (Zn), suggesting oral supplementation of Zn as a therapeutic strategy. To protect patients, it is exceedingly important to monitor blood serum concentration of Zn during supplementation in order to ensure normal physiological levels and watch for heavy metal toxicity due to over supplementation. Current quantification methods typically involve the use of external laboratory facilities and turnaround times ranging from hours to days. This paper presents an improved Point-of-Care device centered on a three electrode Cu based sensor that uses Anodic Stripping Voltammetry (ASV) for rapid electrochemical measurement of Zn in serum. This next-generation device incorporates two major improvements over those presented previously - an evolution to a single printed circuit board (PCB) design, and the incorporation of automated concentration detection. The sensor is able to produce quantification results in approximately 6 minutes.

With 42,000 cases reported annually in the United States and an approximate 10% mortality rate, [1] pediatric septic shock is a major health problem that is often difficult to treat effectively. Several studies have shown that children experiencing pediatric septic shock often have critically low levels of serum zinc (Zn), suggesting supplementation of Zn to be an effective therapeutic strategy. However, to protect the safety and well-being of the patient, it is extremely important to monitor blood serum concentration of Zn during supplementation in order to ensure that levels remain at or near the physiological norm and thus minimize the risk of heavy metal toxicity from over supplementation. Current methods for quantifying Zn in serum typically require sending serum samples to external laboratory facilities resulting in turnaround times ranging from hours to a few days. Therefore, timely monitoring of Zn levels in serum is often not possible in the clinical setting which ultimately limits the ability to use Zn supplementation as a therapeutic intervention. This paper reports on the development of a Point-of-Care device for rapid electrochemical measurement of Zn in serum. The device is centered on a three electrode sensor which uses Anodic stripping voltammetry (ASV) for sensing Zn levels. The Cu based sensor is read using a reader that has been developed using commercially available embedded system parts in combination with custom analog circuitry that is able to produce quantification results in approximately 6 minutes.

Although primary open anatomic reduction and stable internal fixation has become a standard treatment principle of Lisfranc joint injuries, there are still some debates existed among surgeons as to the most appropriate treatment of this injury. The aim of this cohort study was to analyze the early (mean, 3.2 years) clinical and radiographic outcomes of one surgeon's experience associated with a standardized protocol of open reduction and internal fixation using headless compression screws (HCS) in a consecutive series of Chinese patients with Lisfranc joint injuries.This study is to retrospectively evaluate the clinical and radiographic outcomes of a series of Chinese patients with Lisfranc joint injuries that underwent open reduction and internal fixation with HCS.There were 29 patients (30 feet) included in our study. The average score of American Orthopaedic Foot and Ankle Society Midfoot score and the Visual Analog Pain Scale were 80.6 and 2.4 points at the final follow-up point, respectively. Anatomic initial reduction was obtained in 26 patients (27 feet, 90%). At the last follow-up point, only one case had the loss of reduction. Posttraumatic osteoarthritis was observed in 10 patients (10 feet, 33%), and 2 of them (2 feet, 7%) were scheduled for arthrodesis because of persistent pain.Our results have shown that fixation of an unstable tarsometatarsal joint with AO 3.0 mm HCS can provide the firm stability, the precise reduction of the joint, and satisfactory short-term clinical and radiographic outcomes without any screw breakage, although posttraumatic osteoarthritis in the midfoot is still a significant challenge for orthopedic surgeons.

Although xenotropic murine leukemia virus-related virus (XMRV) has been previously linked to prostate cancer and myalgic encephalomyelitis/chronic fatigue syndrome, recent data indicate that results interpreted as evidence of human XMRV infection reflect laboratory contamination rather than authentic in vivo infection. Nevertheless, XMRV is a retrovirus of undefined pathogenic potential that is able to replicate in human cells. Here we describe a comprehensive analysis of two male pigtailed macaques ( Macaca nemestrina ) experimentally infected with XMRV. Following intravenous inoculation with >10 10 RNA copy equivalents of XMRV, viral replication was limited and transient, peaking at ≤2,200 viral RNA (vRNA) copies/ml plasma and becoming undetectable by 4 weeks postinfection, though viral DNA (vDNA) in peripheral blood mononuclear cells remained detectable through 119 days of follow-up. Similarly, vRNA was not detectable in lymph nodes by in situ hybridization despite detectable vDNA. Sequencing of cell-associated vDNA revealed extensive G-to-A hypermutation, suggestive of APOBEC-mediated viral restriction. Consistent with limited viral replication, we found transient upregulation of type I interferon responses that returned to baseline by 2 weeks postinfection, no detectable cellular immune responses, and limited or no spread to prostate tissue. Antibody responses, including neutralizing antibodies, however, were detectable by 2 weeks postinfection and maintained throughout the study. Both animals were healthy for the duration of follow-up. These findings indicate that XMRV replication and spread were limited in pigtailed macaques, predominantly by APOBEC-mediated hypermutation. Given that human APOBEC proteins restrict XMRV infection in vitro , human XMRV infection, if it occurred, would be expected to be characterized by similarly limited viral replication and spread.

To validated the 12-item Health Status Survey (SF-12) of Chinese version for evaluating health-related quality of life (HRQL) of Kashin-Beck disease (KBD) patients in Aba Tibetan autonomous area, China. 338 adult KBD patients in Rangtang County of Aba area were investigated with SF-12. Principal component analysis with varimax rotation was used to test the original factor pattern. Internal consistency reliability was assessed by using Cronbach’s alpha. “Known groups” construct validity was assessed by comparing SF-12 component scores between respondents hypothesized to differ in health-related variables. Two latent factors were extracted explaining 69.4 % of the variance of the questionnaire. The factor loadings were mostly according with the principle concept, except for “vitality” (VT) and “social functioning” (SF) scales that loaded heavier on physical component. The Cronbach’s alpha coefficient was 0.909 for the physical health domain, 0.900 for the mental health domain, and 0.914 for the whole scale. The SF-12 had satisfactory “known group” validity and could well discriminate the differences between patients and healthy controls and between subgroups divided by age, duration of suffering or number of affected joints. The SF-12 could be used to evaluate the HRQL of adult KBD patients in Aba Tibetan autonomous area in China and with good feasibility, reliability and validity.

Coloured light surrounding a white surface of about equal luminance makes the white surface appear illuminated with an unsaturated light of the complementary colour. In an attempt to discover the neurophysiological basis of such colour induction, we recorded from spectrally opponent cells of the parvocellular layers of the lateral geniculate nucleus (P-LGN) of anaesthetized macaques. Only cells with wide-band (W) spectral sensitivity in the short (S) or long wavelength (L) part of the spectrum (WS, WL) are excited by white spots of light centred on their receptive field. Cells with narrow-band (N) spectral sensitivity (NS, NL) and light-inhibited (LI) cells are inhibited by white light. Therefore, it is likely that the code for white is contained in a balanced excitation of the W cells. The effects of continuous illumination of remote surrounds with different wavelengths on the responses to achromatic light stimuli were investigated. Responses [on minus maintained discharge rate (MDR) or on-minus-off] were determined for white spots (1 - 3 degrees diameter) flashed on the receptive field centre, presented either alone or in the presence of an annular surround of equal luminance (inner diameter 5 degrees; outer diameter 20 degrees ). During red surround illumination the responses of WL cells to white spots tended to be reduced as were those of WS cells during blue surround illumination. Surround illumination with the opponent colour had more variable effects, neither WS nor WL cells showing a significant alteration of their mean response to white during surround illumination with opponent light. Response alterations were to a large extent due to changes in MDR, which increased in WS cells during blue surround illumination and in WL cells during red surround illumination. It is argued that the surround effects on centre responses are due to intraocular stray light rather than lateral connections in the retina. The surround effects also depended to some extent on the size of the test spot. LI cells and the very rare parvocellular panchromatic on-cells showed no chromatic response changes during coloured surround illumination. Inasmuch as the excitation of WS cells, either alone or in combination with NS cell activation, is involved in coding for green and blue, and that of WL cells, in combination with NL cell activation, is involved in coding for red and yellow in perception, the shift of excitation towards one or the other W cell group indicates relatively more red or green signals in the white response, consistent with and in the same direction as colour induction. In addition, the summed population response of WS and WL cells is decreased during surround illumination with any colour including white. This is related to brightness decrease during surround illumination in perception.

We report on experiments which were undertaken in an attempt to clarify mechanisms underlying the contrast effects of chromatic surround illumination on spectral responsiveness of cells in the parvocellular layers of the LGN (P-LGN-cells), that had been demonstrated under standard conditions in the preceding companion paper. The experiments were done in anesthetized macaques (Macaca fascicularis). In some neurons, S-potentials were recorded together with the post-synaptic action potentials, and all effects seen in P-LGN-cells were present already in their retinal afferents indicating their retinal origin. The responsiveness of the cells for center stimuli of different wavelengths and during illumination of the receptive field center or the outer surround was determined. Continuous outer surround illumination altered maintained discharge rate (MDR), sensitivity and gain of P-LGN and retinal ganglion cells in the same way and empirically not distinguishable from direct illumination of the receptive field. Responses to surround flashes showed the same dependence on spectral composition as those to center flashes. Adaptation and excitation caused by outer surround illumination (inner diameter 5 degrees, outer diameter 20 degrees) were, in the average, ten times weaker than those exerted by light of the same spectral composition shone directly into the receptive field. Surround effects decreased proportional to r-2. Excitation by outer surround flashes was reduced by adaptation of the receptive field center in the same manner as responses to center flashes. The findings indicate that outer surround light has a direct excitatory and adaptive effect on the excitatory or inhibitory cones feeding into the receptive field. This indicates that straylight from the surround into the center could be responsible for the adaptive and excitatory effects of surround illumination. The straylight fraction from the remote surround into the receptive field must be higher, however, than that estimated from the psychophysically determined point spread function. It comes closer to earlier direct straylight measurements in excised eyes, but may be enhanced by chromatic aberration. If a surround of excitatory colour is flashed simultaneously with an excitatory center stimulus, additivity of center and surround excitation is observed only at low center intensities, while at higher center intensities the gain for center excitation is reduced similar to adaptive gain control. This could be explained by lateral interaction through horizontal connections in the retina, which decays within seconds, while adaptation of the cones feeding into the receptive field center is fully effective only after about 3 s.(ABSTRACT TRUNCATED AT 400 WORDS)

Background: With osteoporosis emerged as one of the most important health issues, more and more investigations are focusing on osteoporotic fracture healing. However, there are few studies on the changes of microstructure and mineralized tissue of newly formed callus. Objective: We established an osteoporotic fracture rat model to evaluate the changes of microstructure and mineralized tissue during osteoporotic fracture healing. Materials and methods: A mid-shaft femur fracture model was established 12 weeks after ovariectomy as an osteoporotic fracture group (OPF group). Femurs were then harvested at 4 weeks, 8 weeks and 12 weeks after fracture for peripheral quantitative computed tomography (pQCT), micro-computed tomography (MicroCT), histology and biomechanical test. A sham-operated group was used for comparison, i.e. the normal fracture group (NF group). Results: The pQCT-derived total external callus area in the OPF group was smaller than that in the NF group at 4 weeks after fracture (Pb0.05), whereas it was 21% larger in the OPF group than that in the NF group at 12 weeks after fracture (Pb0.01). The pQCT-derived bone mineral density in the OPF group was significantly inferior to the NF group at all the time points (Pb0.05 for all the time points, respectively). MicroCT data, at 12 weeks after fracture, showed the total callus, bony callus, and newly formed bone was approximately 20% lower in the OPF group than that in the NP group, and the total connectivity was 56% lower in the OPF group as compared to the NF group. Biomechanical test data, at 12 weeks after fracture, showed that the failure load of the left femur of OPF group was 17% less compared to that of the NF group (Pb0.01), and 15% lower bending stiffness (Pb0.05), 20% lower bending stress (Pb0.01), and 28% lower energy at failure (Pb0.01) were observed in the OPF group as compared to the NF group. Conclusion: The decrease in mineralized tissue and the not well connected microstructure in newly formed callus may explain the decline of mechanical impairment of fracture healing in the ovariectomized rats.

A wide class of sensory neurons demonstrates spontaneous oscillatory activity. Moreover, some thermosensitive neurons, for example, electroreceptors of the paddlefish, dogfish, the warm and cold receptors of rat and cat and the caudal photoreceptor of the crayfish, display complicated bifurcation sequences of the spike train patterns as the control parameter, e. g. the temperature, changes. Recent experiments also revealed the existence of low‐dimensional chaotic behavior of some thermoreceptors. We study a rather unusual behavior of a bursting neuron exhibiting an explosion of interspike intervals at a certain temperature value. This phenomenon can be qualitatively demonstrated with electro‐physiological experiments with the caudal photoreceptor of the crayfish. Furthermore we investigate a modified Hodgkin‐Huxley model to understand the experimentally observed abrupt increase of the interspike intervals. We identify this transition with a homoclinic bifurcation of a saddle‐focus equilibrium state which is embedded in the chaotic attractor of the system.

1. The caudal photoreceptor (CPR) interneurons in the sixth abdominal ganglion of the crayfish are complex, multi-modal interneurons. These cells respond directly to light with tonic spike discharges, and they integrate synaptic input from an array of fili-form mechanoreceptors on the tailfan. They also provide input to rostral command centers, inducing backward walking at high firing frequencies, and thus directly influence behavior. 2. We recorded CPR activity in response to weak hydrodynamic stimulation of the tailfan mechanoreceptors while under varying intensities of light shined on the sixth ganglion. Spike trains were characterized according to the mean discharge rate (MDR) and the power spectrum from which the signal-to-noise ratio (SNR) was calculated. 3. Illumination of the CPR enhances the efficiency of transmitting mechanosensory signals. It does so by increasing the SNR of mechanosensory input received from tailfan receptors. A sevenfold, nonlinear increase in the SNRs was observed with increasing light intensity, an effect especially pronounced for weak hydrodynamic stimuli. In comparison with the dark, illumination of the ganglion lowered the hydrodynamic threshold and heightened the response to suprathreshold stimulation. Unlike the SNR, the MDR is little affected by mechanosensory input. 4. These results are compared with simulated electronic activity from an analogue threshold model and are discussed with respect to the mechanism of stochastic resonance.

Forty-three single fibres were recorded from cat optic tract. They were tested with flashing lines of different lengths and/or spots of different dimensions. The area of centre excitation and of surround inhibition were represented in the length (or dimension)-response functions by the steep rising and falling phases, respectively. For most of the cells, a secondary gentle rise was seen when the stimulus extended beyond the inhibitory surround, indicating an extensive disinhibitory region (DIR) outside the classical receptive field (RF). Disinhibition appeared and developed concurrently with surround inhibition at stimulus intensities between 3 and 30 cd/m2, being represented in the phasic or the tonic component of responses depending on the cell type recorded.