New three‐dimensional head‐mounted display system,TMDU‐S‐3D system,for minimally invasive surgery application: Procedures for gasless single‐port radical nephrectomy

We present an application of a new three‐dimensional head‐mounted display system that combines a high‐definition three‐dimensional organic electroluminescent head‐mounted display with a high‐definition three‐dimensional endoscope to minimally invasive surgery, using gasless single‐port radical nephrectomy procedures as a model. This system presents the surgeon with a higher quality of magnified three‐dimensional imagery in front of the eyes regardless of head position, and simultaneously allows direct vision by moving the angle of sight downward. It is also significantly less expensive than the current robotic surgery system. While carrying out gasless single‐port radical nephrectomy, the system provided the surgeon with excellent three‐dimensional imagery of the operative field, direct vision of the outside and inside of the patient, and depth perception and tactile feedback through the devices. All four nephrectomies were safely completed within the operative time, blood loss was within usual limits and there were no complications. The display was light enough to comfortably be worn for a long operative time. Our experiences show that the three‐dimensional head‐mounted display system might facilitate maneuverability and safety in minimally invasive procedures, without prohibitive cost, and thus might mitigate the drawbacks of other three‐dimensional vision systems. Because of the potential benefits that this system offers, it deserves further refinements of its role in various minimally invasive surgeries.     

MicroRNA‐199a‐3p,microRNA‐193b,and microRNA‐320c are correlated to aging and regulate human cartilage metabolism

MicroRNAs (miRNAs) are small RNAs of ～22 base pairs that regulate gene expression. We harvested cartilage tissue from patients with polydactylism, anterior cruciate ligament injury, and osteoarthritis undergoing total knee arthroplasty and used microarrays to identify miRNAs whose expression is upregulated or downregulated with age. The results were assessed by real‐time PCR and MTT assay in a mimic group, in which synthetic double‐stranded RNA from the isolated miRNA was transfected to upregulate expression, and in an inhibitor group, in which the miRNA was bound specifically to downregulate expression. The expression of two miRNAs (miR‐199a‐3p and miR‐193b) was upregulated with age and that of one miRNA (miR‐320c) was downregulated with age. A real‐time PCR assay showed that type 2 collagen, aggrecan, and SOX9 expression were downregulated in the miR‐199a‐3p mimic group but was upregulated in the inhibitor group. Similar results were observed for miR‐193b. By contrast, ADAMTS5 expression was downregulated in the miR‐320c mimic group and upregulated in the inhibitor group. Cell proliferative activity was upregulated significantly in the miR‐193b inhibitor group compared with the control group. We believe that miR‐199a‐3p and miR‐193b are involved in the senescence of chondrocytes, and miR‐320c is involved in the juvenile properties of chondrocytes. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1915–1922, 2012     

Excellent Clinical Outcomes From a National Donation‐After‐Determination‐of‐Cardiac‐Death Lung Transplant Collaborative

Donation‐after‐Determination‐of‐Cardiac‐Death (DDCD) donor lungs can potentially increase the pool of lungs available for Lung Transplantation (LTx). This paper presents the 5‐year results for Maastricht category III DDCD LTx undertaken by the multicenter Australian National DDCD LTx Collaborative. The Collaborative was developed to facilitate interaction with the Australian Organ Donation Authority, standardization of definitions, guidelines, education and audit processes. Between 2006 and 2011 there were 174 actual DDCD category III donors (with an additional 37 potentially suitable donors who did not arrest in the mandated 90 min postwithdrawal window), of whom 71 donated lungs for 70 bilateral LTx and two single LTx. In 2010 this equated to an “extra” 28% of donors utilized for LTx. Withdrawal to pulmonary arterial flush was a mean of 35.2 ± 4.0 min (range 18–89). At 24 h, the incidence of grade 3 primary graft dysfunction was 8.5%[median PaO₂/FiO₂ ratio 315 (range 50–507)]. Overall the incidence of grade 3 chronic rejections was 5%. One‐ and 5‐year actuarial survival was 97% and 90%, versus 90% and 61%, respectively, for 503 contemporaneous brain‐dead donor lung transplants. Category III DDCD LTx therefore provides a significant, practical, additional quality source of transplantable lungs.     

Optimism,self‐efficacy and information processing of threat‐ and well‐being‐related stimuli

The purpose of this study was to examine whether information bias associated with dispositional optimism and generalized self‐efficacy can account for the link between general expectations and well‐being. A modified Stroop task was used in this study. Our hypothesis was that individuals with high self‐efficacy expectations or dispositional optimism would show greater bias towards well‐being‐related stimuli, whereas individuals with low self‐efficacy or optimism would exhibit bias towards threat‐related stimuli. A secondary hypothesis was that both self‐efficacy and optimism would act as mediators of the latency, perceived distress relationship. One hundred and two undergraduate students participated in the study. After controlling for daily mood, the results showed that individuals high in optimism and self‐efficacy showed greater informational bias towards well‐being‐related stimuli. The low self‐efficacy group exhibited greater bias towards threat‐related stimuli. Also, consistent with our hypothesis, optimism and self‐efficacy mediated the relationship between the Stroop colour‐naming latencies and perceived distress. These findings suggest that associations, which refer to automatic processes, may form an additional way through which expectations are related to functioning. Copyright © 2007 John Wiley & Sons, Ltd.     

Single‐Dose,Randomized, Double‐Blind,Placebo‐Controlled Study of ACE‐011 (ActRIIA‐IgG1) in Postmenopausal Women

The effects of ACE‐011 on safety, pharmacokinetics, and bone biomarkers were evaluated in healthy, postmenopausal women. Our data indicate that ACE‐011 results in a sustained increase in biomarkers of bone formation and reduction in markers of bone resorption. The activin type IIA receptor (ActRIIA) is the high‐affinity receptor for activin. ACE‐011 is a dimeric fusion protein consisting of the extracellular domain of the human ActRIIA linked to the Fc portion of human IgG1. ACE‐011 binds to activin, preventing activin from binding endogenous receptors. A randomized, double‐blind, placebo‐controlled study was conducted to evaluate the safety and tolerability of ACE‐011. Forty‐eight healthy, postmenopausal women were randomized to receive either a single dose of ACE‐011 or placebo and were followed for 4 mo. Dose levels ranged from 0.01 to 3.0 mg/kg intravenously and from 0.03 to 0.1 mg/kg subcutaneously. Safety and pharmacokinetic (PK) analyses and the biological activity of ACE‐011, as assessed by markers of bone turnover, and follicle stimulating hormone (FSH) levels were measured. No serious adverse events (AEs) were reported. AEs were generally mild and transient. The PK of ACE‐011 was linear over the dose range studied, with a mean half‐life of 24–32 days. The absorption after subcutaneous dosing was essentially complete. ACE‐011 caused a rapid and sustained dose‐dependent increase in serum levels of bone‐specific alkaline phosphatase (BSALP) and a dose‐dependent decrease in C‐terminal type 1 collagen telopeptide (CTX) and TRACP‐5b levels. There was also a dose‐dependent decrease in serum FSH levels consistent with inhibition of activin. ACE‐011 is a novel agent with biological evidence of both an increase in bone formation and a decrease in bone resorption. ACE‐011 may be an effective therapy in a variety of diseases involving bone loss.     

Evaluation of Hyphecan (1‐4,2‐acetamide‐deoxy‐B‐D‐glucan polymer) on wound healing in a rodent model

Objective: To evaluate the effect of an artificial skin Hyphecan (1‐4,2‐acetamide‐deoxy‐B ‐D ‐glucan polymer) on wound healing in a rodent model. Materials and Method: The prospective study was conducted at a basic science laboratory at a tertiary teaching hospital. Two 4 cm × 4 cm full‐thickness wounds were created on the dorsal surface of 10 Spraque–Dawley rats and covered with Hyphecan and Kaltostat, respectively. Wounds were examined and measured on days 4, 10, 21 and 28, and would continue after day 28 until healed up completely. Punch biopsies (3 mm) were taken on days 4, 10 and 28 for histological examination of the response of healing and repair. Results: Despite the fact that the wound healing rate was similar for both groups on days 4, 10, 21 and 28, the average healing time for the Hyphecan group (29.1 ± 1.7 days) was significantly shorter statistically (P = 0.03) than the Kaltostat group (30.7 ± 2.8 days). Conversely, the marked healing response elicited by Hyphecan on day 4 persisted on days 10 and 28 in contrast to Kaltostat, which had only a mild degree of healing response on days 10 and 28. The study suggests that wounds treated by Hyphecan heal faster than Kaltostat. Conclusion: The findings provide basic scientific evidence supporting the clinical use of Hyphecan in different wounds and might also reduce the cost of wound management as Hyphecan is cheaper than Kaltostat and requires a shorter treatment time.      

Once‐daily,prolonged‐release tacrolimus vs twice‐daily,immediate‐release tacrolimus in de novo living‐donor liver transplantation: A Phase 4, randomized,open‐label,comparative, single‐center study

Randomized, open‐label, comparative, single‐center, Phase 4, 24‐week study comparing pharmacokinetics (PK), safety, and efficacy of once‐daily, prolonged‐release tacrolimus (PR‐T) with twice‐daily, immediate‐release tacrolimus (IR‐T) in adult de novo living‐donor liver transplant (LDLT) recipients in Korea. All patients received intravenous tacrolimus from Day 0 (transplantation) for 4 days and were randomized (1:1) to receive oral PR‐T or IR‐T from Day 5. PK profiles were taken on Days 6 and 21. Primary endpoint: area under the concentration‐time curve over 24 hour (AUC_0‐24). Predefined similarity interval for confidence intervals of ratios: 80%‐125%. Secondary endpoints included: tacrolimus concentration at 24 hour (C₂₄), patient/graft survival, biopsy‐confirmed acute rejection (BCAR), treatment‐emergent adverse events (TEAEs). One‐hundred patients were included (PR‐T, n = 50; IR‐T, n = 50). Compared with IR‐T, 40% and 66% higher mean PR‐T daily doses resulted in similar AUC_0‐24 between formulations on Day 6 (PR‐T:IR‐T ratio of means 96.8%), and numerically higher AUC_0‐24 with PR‐T on Day 21 (128.8%), respectively. Linear relationship was similar between AUC_0‐24 and C₂₄, and formulations. No graft loss/deaths, incidence of BCAR and TEAEs similar between formulations. Higher PR‐T vs IR‐T doses were required to achieve comparable systemic exposure in Korean de novo LDLT recipients. PR‐T was efficacious; no new safety signals were detected.     

Substrain‐specific differences in bone parameters,alpha‐2‐macroglobulin circulating levels,and osteonecrosis incidence in a rat model

Osteonecrosis of the femoral head (ONFH) is a potentially devastating complication that occurs in up to 40% of young adults receiving chronic glucocorticoid (GC) therapy. Through a validated GC therapy rat model, we have previously shown that Wistar Kyoto ( WK) rats exhibit a genetic susceptibility to GC‐induced ONFH compared to Sasco Fischer (F344) rats. We have undertaken this study in order to investigate differences between these two strains for their bone parameters, alpha‐2‐macroglobulin (A2M) circulating levels and incidence of GC‐induced osteonecrosis of the femoral head. WK and F344 rats were treated either with 1.5 mg/kg/day of prednisone or placebo for 6 months. Blood was taken every month. The femoral heads were harvested for histological examination to detect ONFH and analyzed with micro‐computed tomography. After 3 months of GC‐therapy, plasma A2M was elevated in treated rats only. GC‐treated WK rats exhibited histological evidence of early ONFH through higher rates of cellular apoptosis and empty osteocyte lacunae in the subchondral bone compared to placebos and to F344 rats. Furthermore, micro‐CT analysis exhibited femoral head collapse only in GC‐treated WK rats. Interestingly, GC‐treated F344 rats exhibited significant micro‐CT changes, but such changes were less concentrated in the articular region and were accompanied histologically with increased marrow fat. These µCT and histological findings suggest that elevated A2M serum level is not predictive and suitable as an indicative biomarker for early GC‐induced ONFH in rodents. Elevated A2M levels observed during GC treatment suggests that it plays role in the host reparative response to GC‐associated effects. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1183–1194, 2017.

     

Comparison of the effect of intra‐tendon applications of recombinant human platelet‐derived growth factor‐BB,platelet‐rich plasma,steroids in a rat achilles tendon collagenase model

This study compared the effect of intra‐tendon (IT) delivery of recombinant human platelet‐derived growth factor‐BB (rhPDGF‐BB), platelet‐rich plasma (PRP) and corticosteroids in a rat tendinopathy model. Seven days after collagenase induction of tendinopathy, a 30‐µl IT injection was administered. Treatments included: saline; 3 µg rhPDGF‐BB; 10 µg rhPDGF‐BB; PRP; and 300 µg triamcinolone acetonide (TCA). Outcomes were assessed 7 and 21 days after treatment. All groups exhibited good to excellent repair. Relative to saline, cell proliferation increased 65% in the 10 µg rhPDGF‐BB group and decreased 74% in the TCA group; inflammation decreased 65% in the TCA group. At 7 days, maximum load‐to‐failure was increased in the 3 µg rhPDGF‐BB group relative to saline, PRP, and TCA (p < 0.025). On day 21, maximum load‐to‐rupture was increased in the 10 µg rhPDGF‐BB group relative to saline, PRP, and TCA (p < 0.035) and in the 3 µg rhPDGF‐BB group compared to saline and TCA (p < 0.027). Stiffness in the 10 µg rhPDGF‐BB group was increased compared to saline, PRP, and TCA (p < 0.038). Histology demonstrated similar repair in all groups. PRP and TCA did not improve mechanical properties compared to saline. Injections of rhPDGF‐BB increased maximum load‐to‐failure (3 and 10 µg) and stiffness (10 µg) relative to controls and commonly used treatments. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:145–150, 2014.     

Potential pathological role of pro‐inflammatory cytokines (IL‐6, TNF‐α, and IL‐17) in xenotransplantation

The major limitation of organ transplantation is the shortage of available organs from deceased human donors which leads to the deaths of thousands of patients each year. Xenotransplantation is considered to be an effective way to resolve the problem. Immune rejection and coagulation dysfunction are two major hurdles for the successful survival of pig xenografts in primate recipients. Pro‐inflammatory cytokines, such as IL‐6, TNF‐α, and IL‐17, play important roles in many diseases and in allotransplantation. However, the pathological roles of these pro‐inflammatory cytokines in xenotransplantation remain unclear. Here, we briefly review the signaling transduction and expression regulation of IL‐6, TNF‐α, and IL‐17 and evaluate their potential pathological roles in in vitro and in vivo models of xenotransplantation. We found that IL‐6, TNF‐α, and IL‐17 were induced in most in vitro or in vivo xenotransplantation model. Blockade of these cytokines using gene modification, antibody, or inhibitor had different effects in xenotransplantation. Inhibition of IL‐6 signaling with tocilizumab decreased CRP but did not increase xenograft survival. The one possible reason is that tocilizumab can not suppress IL‐6 signaling in porcine cells or organs. Other drugs which inhibit IL‐6 signaling need to be investigated in xenotransplantation model. Inhibition of TNF‐α was beneficial for the survival of xenografts in pig‐to‐mouse, rat, or NHP models. Blockade of IL‐17 using a neutralizing antibody also increased xenograft survival in several animal models. However, the role of IL‐17 in the pig‐to‐NHP xenotransplantation model remains unclear and needs to be further investigated. Moreover, blockade of TNF‐α and IL‐6 together has got a better effect in pig‐to‐baboon kidney xenotransplantation. Blockade two or even more cytokines together might get better effect in suppressing xenograft rejection. Better understanding the role of these cytokines in xenotransplantation will be beneficial for choosing better immunosuppressive strategy or producing genetic modification pig.     

Double‐blind,randomised, placebo‐controlled trial on the effect of L‐carnitine and L‐acetylcarnitine on sperm parameters in men with idiopathic oligoasthenozoospermia

Carnitine is essential for energy metabolism and spermatozoa maturation. Combining L‐carnitine and L‐acetylcarnitine with micronutrients has been investigated as a treatment for infertility in men. We evaluated the effects of a therapeutic formulation, Proxeed Plus, on sperm parameters in oligoasthenozoospermic men. This prospective, randomised, double‐blind, placebo‐controlled clinical trial involved 175 males (19–44 years) with idiopathic oligoasthenozoospermia who failed to impregnate their partners (12 months). Males received Proxeed Plus or placebo for 3 and 6 months. Sperm volume, progressive motility and vitality significantly (p < 0.001) improved after 6 months compared to baseline. Sperm DNA fragmentation index significantly decreased compared to baseline (p < 0.001) and the 3‐month therapy (p = 0.014) in treated men. Increased seminal carnitine and α‐glucosidase concentration also positively correlated with improved progressive motility. Decreased DNA fragmentation index was the good predictor of progressive sperm motility >10%, and simultaneous measurement of changes in sperm vitality and DNA fragmentation index gave the highest probability of sperm motility 10% (AUC = 0.924; 95% CI = 0.852–0.996; p < 0.001). Logistic regression analyses revealed DNA fragmentation index decrease as the only independent predictor of sperm motility 10% (OR = 1.106; p = 0.034). We have demonstrated the beneficial effects of carnitine derivatives on progressive motility, vitality and sperm DNA fragmentation. Combining metabolic and micronutritive factors is beneficial for male infertility.