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Objectives: (1) To characterize the average trajectories of frailty over time in Chinese community-dwelling older adults; (2) To assess the effects of neighborhood structural and individual characteristics on frailty progression., Design: A nationally representative prospective cohort study., Setting: Communities in 28 provinces, China., Participants: 6238 respondents aged 60 and above in 447 communities from four waves of the China Health and Retirement Longitudinal Study., Measurements: Frailty was measured using the 61-item Frailty Index (FI)., Results: The trajectory of FI was nonlinear, with an average growth rate of 0.025 that significantly slows down at the rate of 0.002 per year. Older, male, and uninsured respondents showed faster rates of growth in FI over time than younger, female, and insured counterparts. Respondents living in neighborhoods with a higher percentage of the older population and rural villages showed slower rates of growth in FI over time., Conclusion: Expanding health insurance coverage and keeping a high clustering of the elderly in neighborhoods may be the potential strategies for population-level frailty prevention and interventions., Competing Interests: The authors declare no conflicts of interests.

Engineering change is a significant cost sink in many projects. While avoiding and mitigating the risk of change is the ideal approach, mistakes and improvements are recognized inevitably as more is learned over time about the quality of the decisions made in a product's design. This paper presents a feasibility and performance analysis of automating engineering change requests to demonstrate the promise for increasing speed, efficiency, and effectiveness of product-lifecycle-wide engineering-change-request processes. To explore this idea, a comparatively simple case study is examined both to mimic the reduced set of alterable aspects of a typical change request and to highlight the need of appropriate search algorithms as brute force methods quickly prohibitively resource intensive. Although such cases may seem trivial for human agents, with the volume of expected change requests in a typical facility, the potential opportunity gain by eliminating or reducing the amount of human effort in low level change requests accumulate into significant returns for industry on time and money. Within this work, the genetic algorithm is selected to demonstrate feasibility due to its broad scope of applicability and low barriers to deployment. Future refinement of this or other sophisticated algorithms leveraging the nature of the standard representations and qualities of alterable design features could produce tools with strong implications for process efficiency and industry competitiveness in the execution of its projects.

Iron is one of the most studied chemical elements due to its sociotechnological and planetary importance; hence, understanding its structural transition dynamics is of vital interest. By combining a short pulse optical laser and an ultrashort free electron laser pulse, we have observed the subnanosecond structural dynamics of iron from high-quality x-ray diffraction data measured at 50-ps intervals up to 2500 ps. We unequivocally identify a three-wave structure during the initial compression and a two-wave structure during the decaying shock, involving all of the known structural types of iron (α-, γ-, and ε-phase). In the final stage, negative lattice pressures are generated by the propagation of rarefaction waves, leading to the formation of expanded phases and the recovery of γ-phase. Our observations demonstrate the unique capability of measuring the atomistic evolution during the entire lattice compression and release processes at unprecedented time and strain rate., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Recent advances in biochip technologies that connect next-generation sequencing (NGS) to real-world problems have facilitated breakthroughs in science and medicine. Because biochip technologies are themselves used in sequencing technologies, the main strengths of biochips lie in their scalability and throughput. Through the advantages of biochips, NGS has facilitated groundbreaking scientific discoveries and technical breakthroughs in medicine. However, all current NGS platforms require nucleic acids to be prepared in a certain range of concentrations, making it difficult to analyze biological systems of interest. In particular, many of the most interesting questions in biology and medicine, including single-cell and rare-molecule analysis, require strategic preparation of biological samples in order to be answered. Answering these questions is important because each cell is different and exists in a complex biological system. Therefore, biochip platforms for single-cell or rare-molecule analyses by NGS, which allow convenient preparation of nucleic acids from biological systems, have been developed. Utilizing the advantages of miniaturizing reaction volumes of biological samples, biochip technologies have been applied to diverse fields, from single-cell analysis to liquid biopsy. From this perspective, here, we first review current state-of-the-art biochip technologies, divided into two broad categories: microfluidic- and micromanipulation-based methods. Then, we provide insights into how future biochip systems will aid some of the most important biological and medical applications that require NGS. Based on current and future biochip technologies, we envision that NGS will come ever closer to solving more real-world scientific and medical problems.

Cell death-inducing DFF45-like effector (CIDE) B is a member of the CIDE family of apoptosis-inducing factors. In the present study, we detected a single nucleotide polymorphism (SNP), c.414G>A, which corresponds to the synonymous SNP 414Arg, in CIDE-B in the Berkshire pigs. We also analyzed the relationships between the CIDE-B SNP and various meat quality traits. The SNP was significantly associated with post-mortem pH 24h , water-holding capacity (WHC), fat content, protein content, drip loss, post-mortem temperature at 12 h (T12) and 24 h (T24) in a co-dominant model (P < 0.05). A significant association was detected between the SNP and post-mortem pH 24h , fat content, protein content, drip loss, shear force, and T24 in gilts; and color parameter b*, WHC, and T24 in barrows (P < 0.05). The SNP was significantly correlated with the fat content, and CIDE-B mRNA expression was significantly upregulated during the early stage of adipogenesis, suggesting that CIDE-B may contribute towards initiation of adipogenesis (P < 0.05). Furthermore, CIDE-B mRNA was strongly expressed in the liver, kidney, large intestine, and small intestine, and weakly expressed in the stomach, lung, spleen, and white adipose tissue. These results indicate that the CIDE-B SNP is closely associated with meat quality traits and may be a useful DNA marker for improving pork quality.

Unlabelled: This retrospective observational study analyzed lesions with regard to healing trends and cost of materials., Materials and Methods: The observed lesions were mostly postsurgical or stage IV pressure ulcers in patients with serious morbidity. The wounds were treated with a hydrokinetic fiber dressing (sorbion Sachet S, sorbion Gmbh & Co, a BSN medical company, Senden, Germany) (n = 26) or negative pressure wound therapy (NPWT) (n = 16)., Results: Primary healing trends (ie, reduction of wound size, change from necrosis to granulation tissue, and change from granulation tissue to epithelium) and secondary healing trends (ie, periwound conditions) were similar for wounds treated with the hydrokinetic dressing when compared to wounds treated with NPWT. Cost of materials was substantially lower for wounds treated with the hydrokinetic fiber dressing compared to the NPWT, with cost reductions of $1,640 (348%) to $2,242 (1794%) per wound, depending on the criteria used for the analysis., Conclusion: In this set of wounds, the hydrokinetic fiber dressing was shown to lead to similar healing results while providing substantial reductions of the cost of materials. For the types of wounds presented in this observational study, the hydrokinetic fiber dressing seems to be an effective substitution for negative pressure wound therapy.

Background and Purpose: In our previous study, tumor necrosis factor α (TNF-α) was identified as an effective target for sepsis patients (Int J Clin Pract, 68, 2014, 520). TNF-α in cerebrospinal fluid (CSF) was also investigated for its utility in the differential diagnosis of bacterial and aseptic meningitis. However, there has been neither definite nor convincing evidence so far. Here the overall diagnostic accuracy of TNF-α in differentiation between bacterial and aseptic meningitis was evaluated through the meta-analysis of diagnostic tests., Methods: The sensitivity, specificity and other measures of accuracy were pooled using random effect models. Summary receiver operating characteristic curves were used to assess overall test performance. Publication bias was evaluated using funnel plots, and sensitivity analysis was also introduced., Results: A total of 21 studies involving bacterial meningitis (678) and aseptic meningitis (694) involved a total of 1372 patients. The pooled sensitivity and specificity for the TNF-α test were 0.83 [95% confidence interval (CI) 0.80-0.86, I(2)  = 65.1] and 0.92 (95% CI 0.89-0.94, I(2)  = 61.8), respectively. The positive likelihood ratio was 12.05 (95% CI 7.41-19.60, I(2)  = 36.5), the negative likelihood ratio was 0.17 (95% CI 0.13-0.24, I(2)  = 59.4), and TNF-α was significantly associated with bacterial meningitis, with a diagnostic odds ratio of 49.84 (95% CI 28.53-87.06, I(2)  = 47.9). The overall accuracy of the TNF-α test was very high with the area under the curve 0.9317. Publication bias was absent, and sensitivity analysis suggested that our results were highly stable., Conclusions: Our meta-analysis suggested that TNF-α could be recommended as a useful marker for diagnosis of bacterial meningitis and differential diagnosis between bacterial and aseptic meningitis with high sensitivity and specificity. Thus, hospitals should be encouraged to conduct TNF-α tests in CSF after lumbar puncture., (© 2014 The Author(s) European Journal of Neurology © 2014 EAN.)

Objective: In humans, the role of anti-tumour necrosis factor (TNF)-α therapy in severe sepsis and septic shock is debatable. The aim of this meta-analysis was to determine the efficacy of anti-TNF-α therapies against placebo in patients with severe sepsis or septic shock., Methods: A structured literature search was undertaken to identify randomised controlled trials (RCTs) conducted in patients with severe sepsis or septic shock receiving anti-TNF-α therapy or placebo. A meta-analysis on relative risk (OR) with a 95% confidence interval (95% CI) was performed., Results: Seventeen studies with a total of 8971 patients were included. When all forms of anti-TNF-α therapy were pooled together, there was a significant reduction of 28-day all-cause mortality with respect to placebo (OR = 0.91, 95% CI: 0.83-0.99; p = 0.04). Subgroup analysis showed that anti-TNF-α antibodies (monoclonal and polyclonal) reduced mortality (OR = 0.90, 95% CI: 0.81-0.99; p = 0.04). Monoclonal antibodies enhanced survival (OR = 0.91, 95% CI: 0.82-1.00; p = 0.05), while polyclonal antibodies or receptor blockers did not enhance survival (OR = 0.71, 95% CI: 0.39-1.28, p = 0.25; OR = 0.95, 95% CI: 0.78-1.17, p = 0.65). There was a trend towards better survival in patients with high levels of IL-6 (> 1000 pg/ml) and patients with shock if they were treated with anti-TNF-α therapy (OR = 0.85, 95% CI: 0.72-1.00; OR = 0.80, 95% CI: 0.62-1.04). Publication bias and statistical heterogeneity (I(2)  < 50% and p > 0.1) were absent. Sensitivity analysis suggests that these results are highly stable., Conclusions: This meta-analysis suggests that in patients with severe sepsis (before shock), immunotherapy with anti-TNF-α monoclonal antibodies reduces overall mortality. In patients with shock or high levels of IL-6 (> 1000 pg/ml), anti-TNF-α therapy may improve survival., (© 2014 John Wiley & Sons Ltd.)

Although clinical evidence of endotoxemia has been associated with the development of acute laminitis in hospitalized horses with gastrointestinal diseases and endotoxins have been detected in the circulation of horses with experimentally-induced laminitis, it is unclear what role, if any, endotoxins have play the pathogenesis of the disease. Therefore, in the present study we compared the effects of endotoxin infusion to that of intra-gastric administration of mixed carbohydrate (CHO) on clinical signs of laminitis, plasma concentrations of TNF-α and IL-10, and laminar tissue expression of 20 genes associated with inflammation. Horses were divided into 4 groups: Control (water placebo, n=7), endotoxin infusion (LPS, n=6), CHO/Developmental (30% decrease in central venous pressure, n=6) and CHO/Lame (Obel grade I laminitis, n=7). Horses in the LPS group developed clinical signs consistent with systemic inflammation, had rapid increases in plasma concentrations of both TNF-α and IL-10, and leukopenia, but did not have any changes in laminar tissue expression of the genes associated with inflammation. In contrast, horses administered CHO developed clinical signs consistent with systemic inflammation, had more delayed increases in TNF-α, IL-10 and total leukocyte counts, and had marked increases in laminar tissue expression of the genes associated with inflammation. Only the horses administered CHO developed clinical signs of laminitis, providing additional credence to the concept that factors other than endotoxin are responsible for the changes in laminar tissue gene expression that occur during the development of acute equine laminitis., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objectives: HIV-infected patients are commonly prescribed several medications and are thus at risk for drug interactions that may result in QTc prolongation. We sought (1) to identify the frequency of electrocardiogram (ECG) monitoring (2), to determine the prevalence of drug interactions involving QTc-prolonging medications, and (3) to quantify the prevalence of QTc prolongation., Methods: A cross-sectional study was conducted among HIV-infected adults. Demographics, medications, drug interactions and comorbidities were abstracted from patients' medical records. Abnormal QTc interval was defined per the UK Committee for Proprietary Medicinal Products. Clinical characteristics were compared among ECG recipients and nonrecipients. Among ECG recipients, the prevalence and predictors of QTc prolongation were assessed., Results: Among the 454 patients included in the study, 80.8% were prescribed a medication associated with QTc prolongation and 39% had drug interactions expected to increase QTc prolongation risk. There were 138 patients (30.3%) who received ECG testing. Receipt of ECG monitoring was associated with increasing age, diabetes, increasing total number of medications and gastroesophageal reflux disease. Among ECG recipients, the prevalence of abnormal QTc interval was 27.5%. Chronic kidney disease [prevalence ratio (PR) 3.47; 95% confidence interval (CI) 1.37-8.83; P = 0.009], hepatitis C virus coinfection (PR 2.26; 95% CI 0.97-5.27; P = 0.06) and hypertension (PR 2.11; 95% CI 0.93-4.81; P = 0.07) were independently associated with an abnormal QTc interval., Conclusions: A low frequency of ECG testing was observed, despite a high use of medications associated with QTc prolongation. The risk of abnormal QTc interval was highest among patients with chronic kidney disease, hypertension and hepatitis C virus coinfection., (© 2013 British HIV Association.)

The purpose of this study was to determine the pharmacokinetics (PK) of the 5-HT(2A) receptor antagonist ketanserin in healthy adult horses, and to develop a computational model that could be used to optimize dosing. Plasma concentrations of ketanserin were determined using liquid chromatography with mass spectrometry after single and multiple intravenous administration in the horse. A two-compartment linear pharmacokinetic model described the plasma concentration-time profile of ketanserin after single and multiple doses in healthy horses; the terminal half-life was 11.5 h; steady-state volume of distribution was 10.5 L/kg; AUC was 115 ng · h/mL; and clearance was 0.87 L/h/kg. Model simulations followed by the examination in three healthy horses suggest 0.3 mg/kg q.8 h exhibited linear PK and produced consistent systemic blood concentrations of ketanserin above 3 ng/mL., (© 2011 Blackwell Publishing Ltd.)

Background: Tissue background autofluorescence induced by standard murine diets containing chlorophyll is a significant problem for fluorescence whole-body imaging. However, as red chlorophyll autofluorescence delineates the gastrointestinal (GI) tract in the abdomen of the mouse, it should be possible to dynamically and non-invasively image intestinal motions. Herein, we non-invasively imaged for the first time intestinal motions, such as peristaltic and segmental motions, without an exogenous imaging agent, using red chlorophyll fluorescence., Methods: Mice were illuminated with 660-nm light from a laser diode and autofluorescence at 710 nm was acquired dynamically for 5 min with 200-ms exposure time. Fluorescent imaging data were analyzed to generate a three-dimensional spatiotemporal map to quantitate intestinal motions., Key Results: Peristaltic and segmental motions were observed in vivo in mice. Our quantification showed that the frequency and propagation velocity of peristaltic contractile waves in the small intestine were measured to be 28.6 cycles per min and 1.82 ± 0.56 cm s(-1), respectively., Conclusions & Inferences: This simple, but unexplored imaging technique can provide a means to monitor intestinal motility disorders and response to therapeutic agents., (© 2012 Blackwell Publishing Ltd.)

Background: Absorbance of near-infrared (600-800 nm) light by the tissue components water, melanin, and hemoglobin is minimal. This property allows the use of near-infrared-emitting fluorophores for noninvasive, in vivo, real-time imaging of tissue, without the interference of autofluorescence experienced with imaging in other wavelength ranges. Near-infrared (NIR) fluorescence imaging has been used to noninvasively image lymphatic architecture and pumping function in animals, as well as in humans. The effects of different doses of a NIR dye, indocyanine green (ICG), on lymphatic function have been questioned. This study aims to address these concerns in the context of a mouse inguinal-to-axillary lymphatic imaging model., Methods and Results: We measured lymph propulsive velocity and frequency using an imaging system composed of a laser diode for excitation of the dye, an image intensifier, and an intensified charge-coupled device (ICCD) camera to capture real-time images. At 0.32, 0.645, and 1.3 mM ICG, no significant differences in lymphatic propulsive velocity or frequency were observed. Additionally, the use of other NIR imaging agents did not result in significant differences., Conclusions: The use of different concentrations of ICG and the use of other near-infrared fluorophores for optical imaging of lymphatics does not significantly affect lymphatic propulsive velocity or frequency.

Background: Bortezomib is a proteasome inhibitor with minimal clinical activity as a monotherapy in solid tumours, but its combination with other targeted therapies is being actively investigated as a way to increase its anticarcinogenic properties. Here, we evaluate the therapeutic potential of co-treatment with bortezomib and indole-3-carbinol (I3C), a natural compound found in cruciferous vegetables, in human ovarian cancer., Methods: We examined the effects of I3C, bortezomib and cisplatin in several human ovarian cancer cell lines. Synergy was determined using proliferation assays and isobologram analysis. Cell cycle and apoptotic effects were assessed by flow cytometry. The mechanism of I3C and bortezomib action was determined by RNA microarray studies, quantitative RT-PCR and western blotting. Antitumour activity of I3C and bortezomib was evaluated using an OVCAR5 xenograft mouse model., Results: I3C sensitised ovarian cancer cell lines to bortezomib treatment through potent synergistic mechanisms. Combination treatment with bortezomib and I3C led to profound cell cycle arrest and apoptosis as well as disruptions to multiple pathways, including those regulating endoplasmic reticulum stress, cytoskeleton, chemoresistance and carcinogen metabolism. Moreover, I3C and bortezomib co-treatment sensitised ovarian cancer cells to the standard chemotherapeutic agents, cisplatin and carboplatin. Importantly, in vivo studies demonstrated that co-treatment with I3C and bortezomib significantly inhibited tumour growth and reduced tumour weight compared with either drug alone., Conclusion: Together, these data provide a novel rationale for the clinical application of I3C and bortezomib in the treatment of ovarian cancer.

Objective: Interpregnancy interval (IPI) influences numerous adverse perinatal outcomes. IPI's impact on birth defects is unclear., Study Design: We conducted a population-based case-control study, using 1998 to 2008 administrative data from Washington State. A total of 10, 772 cases, women whose second of two births resulted in an infant with a birth defect, were compared with 32 ,310 controls, women whose second of two births did not result in an infant with a birth defect., Result: Compared with mothers with an IPI between 18 to 23 months, those with an IPI <6 months or ≥60 months had elevated risks of delivering an infant with a birth defect (odds ratio=1.15, 95% confidence interval: 1.03 to 1.28, and odds ratio=1.15, 95% confidence interval: 1.04 to 1.26, respectively)., Conclusion: We observed a J-shaped relationship between IPI and risk of having an infant with a birth defect. As this is one of the first studies to evaluate this association, confirmatory studies are needed.

Background: Sarcoidosis associated pulmonary hypertension (SAPH) is associated with significant morbidity and mortality. There is a paucity of information concerning therapy for this condition., Methods: We performed a prospective, open-label, proof of concept trial of ambrisentan for SAPH. 21 subjects with SAPH received 5 mg/day of ambrisentan for 4 weeks and then 10/mg day for 20 subsequent weeks., Results: No significant change was noted in the 6-minute walk distance over the course of the study (mean change between week 0 and 24: 9.8 +/- 54.6 meters, p: NS). There were also no significant differences between weeks 0 and 24 in terms of dyspnea as measured by the modified Borg scale, serum brain naturetic peptide, diffusing capacity, and quality of life as measured by the Short Form-36. There was a high dropout rate: overall: 11/21, 52%; social reasons: 3/21, 14%; medical reasons: 8/21, 38% because of dyspnea: 6/21, 29% and/or edema: 4/21, 19%. Of those who completed the 24 week study (10/21, 48%), there was an improvement in their WHO functional class and a marked improvement in their health related quality of life as measured by the St. George Respiratory questionnaire (-15.3 +/- 25.0). However both these improvments did not reach statistical significance possibly because of the small sample size., Conclusion: Although ambrisentan was not well tolerated by many of these subjects with SAPH, in those who remained in this 24-week trial, improvements in WHO functional class and in health related quality of life suggested a possible benefit of this drug in selected patients.

Background: After intravenous (i.v.) administration, indocyanine green (ICG) is known to be secreted into bile from the liver via the biliary tracts, enabling fluorescent delineation of the intestine. In addition, ICG is a near-infrared (NIR) excitable fluorophore, capable of providing exogenous contrast for rapid NIR fluorescence imaging. We sought to quantify the intestinal motility using dynamic NIR fluorescence imaging after injection of ICG., Methods: C57BL6 mice were dynamically imaged immediately before and up to 24h after i.v. and intradermal (i.d.) injection of 50 and 10μL of ICG, respectively. Necropsy was also performed 1h postinjection and the entire gastrointestinal tract was isolated and exposed for ex vivo fluorescence imaging., Key Results: The secretion of ICG-laden fluorescent bile into the duodenum was observed in vivo and confirmed in situ. Different patterns of the intestinal motility, such as peristaltic and segmental motions, were dynamically imaged in vivo. Our imaging data showed that the frequency of contractions ranged from 27 to 35cyclesmin(-1) and the propagation velocity of peristaltic waves ranged from 0.82±0.5 to 2.04±1.12cms(-1) ., Conclusions & Inferences: Dynamic NIR fluorescence imaging with injection of ICG can provide a method for diagnostic motility testing for intestinal motility disorders or dysfunction and for potential evaluation of therapeutic agents., (© 2011 Blackwell Publishing Ltd.)

Background: Critically ill horses are susceptible to thrombotic disease, which might be related to increased platelet reactivity and activation., Objectives: To compare the effect of oral clopidogrel and aspirin (ASA) on equine platelet function., Animals: Six healthy adult horses., Methods: Horses received clopidogrel (2 mg/kg p.o. q24h) or ASA (5 mg/kg p.o. q24h) for 5 days in a prospective randomized cross-over design. Platelet aggregation responses to adenosine diphosphate (ADP) and collagen via optical aggregometry, and platelet secretion of serotonin (5HT) and production of thromboxane B(2) (TXB(2) ) by ELISA were evaluated. In horses receiving clopidogrel, high-performance liquid chromatography analysis for clopidogrel and its carboxylic-acid metabolite SR 26334 was performed., Results: SR 26334 was identified in all clopidogrel-treated horses, although the parent compound was not detected. Clopidogrel resulted in decreases in ADP-induced platelet aggregation persisting for 120 hours after the final dose. ADP-induced platelet aggregation decreased from a baseline of 70.2 ± 14.7% to a minimum of 15.9 ± 7.7% 24 hours after the final dose (P < .001). Collagen-induced aggregation decreased from a baseline of 93 ± 9.5% to a minimum of 70.8 ± 16.9% 48 hours after the final dose (P < .001). ASA did not decrease platelet aggregation with either agonist. ASA decreased serum TXB(2) from a baseline value of 1310 ± 1045 to 128 ± 64 pg/mL within 24 hours (P < .01)., Conclusions and Clinical Importance: Clopidogrel effectively decreases ADP-induced platelet aggregation in horses, and could have therapeutic applications for equine diseases associated with platelet activation., (Copyright © 2010 by the American College of Veterinary Internal Medicine.)

Background: Pulmonary vein stenosis is a rare cause of pulmonary hypertension, with variable onset and presentation. One or more of the four pulmonary veins can be primarily or secondarily affected. A five-month-old girl presented with respiratory distress, lethargy and cyanosis requiring intubation., Methods: Echocardiography showed right ventricular dilation, a right ventricular systolic pressure of 97 mmHg, decreased ejection fraction and turbulent flow at the left atrium. Cardiac catheterization revealed stenosis of the left-sided pulmonary veins, for which she underwent a Coles procedure., Results: Postoperatively, there was a transient improvement in the patient's pulmonary hypertension but she subsequently deteriorated. Her prognosis was considered bleak, and a decision was made with the family to withdraw care., Conclusion: Pulmonary vein stenosis is a rare cause of pulmonary hypertension, and is associated with significant morbidity and mortality. Surgical intervention may be of benefit in selected cases. It stands to reason that any treatment will have the best chance of success if completed before the pulmonary hypertension becomes fixed. Early diagnosis depends on a high index of clinical suspicion.

Rationale: Patients with sarcoidosis associated pulmonary hypertension (SAPH) have responded to systemic prostacyclin therapy., Objectives: To determine the rate of response to inhaled prostacyclin, iloprost, in SAPH., Methods: Sarcoidosis patients with pulmonary hypertension and no evidence for left ventricular dysfunction were enrolled in an open label, prospective study. Patients underwent right heart catheterization and six minute walk (6MW) test. Quality of life was evaluated using several instruments, including the Saint George Respiratory Questionnaire (SGRQ). Patients received 5 mcg of inhaled iloprost every 2-3 hours while awake. After four months of therapy, patients underwent repeat cardiac catheterization, 6 MW test, and completed quality of life questionnaires., Measurements and Main Results: Of the 22 patients enrolled, 15 completed all 16 weeks of therapy. The most common reasons for study discontinuation included drug associated cough (3 patients) and compliance with the prescribed number of treatments per day (2 patients). Six patients experienced a 20% or greater decrease in pulmonary vascular resistance (PVR) from baseline with five of these six patients also showing > or = 5 mm Hg reduction in PA mean. Although three patients improved the 6MW distance by at least 30 meters, only one had a decrease in PVR. At 16 weeks a significant decrease was reported in the SGRQ activity score (p = 0.0273), with seven patients having a 4 point or greater decrease., Conclusion: Inhaled iloprost as monotherapy was associated with an improvement in pulmonary hemodynamics and quality of life as assessed by the SGRQ activity score in some sarcoidosis patients with SAPH.

Objective: Performance measures provide important information, but the meaning of change in these measures is not well known. The purpose of this research is to 1) examine the effect of treatment assignment on the relationship between self-report and performance; 2) to estimate the magnitude of meaningful change in 400-meter walk time (400MWT), 4-meter gait speed (4MGS), and Short Physical Performance Battery (SPPB) and 3) to evaluate the effect of direction of change on estimates of magnitude., Design: This is a secondary analysis of data from the LIFE-P study, a single blinded randomized clinical trial. Using change over one year, we applied distribution-based and anchor-based methods for self-reported mobility to estimate minimally important and substantial change in 400MWT, 4MGS and SPPB., Setting: Four university-based clinical research sites., Participants: Sedentary adults aged 70-89 whose SPPB scores were less than 10 and who were able to complete a 400MW at baseline (n=424)., Interventions: A structured exercise program versus health education., Measurements: 400MWT, 4MGS, SPPB., Results: Relationships between self-report and performance measures were consistent between treatment arms. Minimally significant change estimates were 400MWT: 20-30 seconds, 4MGS: 0.03-0.05m/s and SPPB: 0.3 - 0.8 points. Substantial changes were 400MWT: 50-60 seconds, 4MGS: 0.08m/s, SPPB: 0.4 - 1.5 points. Magnitudes of change for improvement and decline were not significantly different., Conclusions: The magnitude of clinically important change in physical performance measures is reasonably consistent using several analytic techniques and appears to be achievable in clinical trials of exercise. Due to limited power, the effect of direction of change on estimates of magnitude remains uncertain.

This study examined the features of 16 complications from 51 distraction lengthenings in the hands of 43 patients. From 1996 to 2006, 24 metacarpals and 27 phalanges were lengthened at a rate of 0.5 and 0.25 mm/day, respectively, using a callus distraction technique. The indications were congenital (33 cases in 27 patients) and traumatic (18 cases in 16 patients) deformities. The average percentage lengthening in the phalanges and metacarpals was 62% (16 mm) and 63% (34 mm), respectively. The distraction rates in the phalanges and metacarpals were 69 and 52 days/cm, respectively. The overall complication rate was 31%. Major complications requiring secondary procedures were non-union (one case), fracture (one case), premature union (one case), angulations (two cases) and dislodgment of pins (two cases). The minor complications encountered were delayed callus formation (four cases), joint stiffness (four cases) and soft tissue thinning (one case). Traumatic deformities had more complications than the congenital ones (nine of 18 cases and seven of 33 cases, respectively). The phalanges had a higher rate of complication than the metacarpals (11 of 27 cases and four of 24 cases, respectively). Most patients with complications except for two children with dislodgment were as satisfied with the final results as those without complications. Although callus distraction in the hand requires a long treatment period and has a relatively high rate of complication, it appears to be effective in achieving adequate bone length. A high level of patient compliance and prompt management of complications by an experienced surgeon are essential for achieving good results.

beta-Thujaplicin (hinokitiol) is a tropolone derivative present in the heartwood of cupressaceous plants and is used as a medicine, a food additive, and a preservative, and in cosmetics as hair tonic. The cultured plant cells of Nicotiana tabacum glycosylated beta-thujaplicin to two glucosides, 4-isopropyltropolone 2-O-beta-D-glucoside (6%) and 6-isopropyltropolone 2-O-beta-D-glucoside (12%), and two gentiobiosides, 4-isopropyltropolone 2-O-beta-D-gentiobioside (2%) and 6-isopropyltropolone 2-O-beta-D-gentiobioside (5%) after 48 h incubation. The use of immobilized cells of N. tabacum in sodium alginate gel much improved the yield of the products; the glycosylation of beta-thujaplicin with immobilized N. tabacum gave the glycoside products, 4-isopropyltropolone 2-O-beta-D-glucoside (11%), 4-isopropyltropolone 2-O-beta-D-gentiobioside (6%), 6-isopropyltropolone 2-O-beta-D-glucoside (20%), and 6-isopropyltropolone 2-O-beta-D-gentiobioside (10%). On the other hand, 4-isopropyltropolone 2-O-beta-D-glucoside (14%), 4-isopropyltropolone 2-O-beta-D-gentiobioside (7%), 6-isopropyltropolone 2-O-beta-D-glucoside (33%), and 6-isopropyltropolone 2-O-beta-D-gentiobioside (13%) were obtained through the biotransformation with immobilized cells in the medium without iron ions. In comparison with the case of bioconversion in the normal medium containing iron ions, removal of iron ions improved the yields of products.

Background and Study Aims: Percutaneous transhepatic cholangioscopy (PTC) is being increasingly used for patients with biliary tract diseases. The aim of this study was to assess the safety of this procedure, and we systematically analyzed PTC-related complications and the risk factors for those complications., Patients and Methods: A total of 364 patients who underwent PTC were included in the study. The initial diagnoses, the indications for PTC, the complications that occurred during the procedures, and the risk factors for these complications were retrospectively analyzed., Results: The overall incidence of complications was 12.9 % for percutaneous transhepatic biliary drainage (PTBD), 12.8 % for tract dilation, and 6.9 % for tract maturation. Complications developed in 58/848 PTC sessions (6.9 %). Cholangitis and bacteremia were associated with PTBD and tract dilation, catheter migration and blockage with tract maturation, and bile duct injury with PTC. Mild complications occurred in 80 patients (22.2 %) during the preparation stages and in 43 sessions (5.1 %) during the PTC itself. Severe complications, including severe hemobilia, hemoperitoneum, rupture of the sinus tract, and ductal injury developed in 17 patients (4.7 %) during the preparation period, and in 15 patients (4.1 %) during PTC. The overall incidence of severe complications along the entire course was 8.2 % (30/364 patients). No patient died or required surgery. Intraductal manipulations, such as electrohydraulic lithotripsy or balloon dilation, and the first session of PTC were risk factors for procedure-related complications., Conclusions: PTC is a relatively safe and well-tolerated method for treating certain biliary tract diseases. Meticulous patient selection and a cooperative team approach are required in order to minimize the incidence of complications and to provide effective management.

Already 94 years ago in 1910, Dr. Hans Christian Jacobaeus performed the first clinical laparoscopic surgery in Stockholm. His pioneering procedure was based on the animal experiments of Georg Kelling (1866-1945), a German physician from Dresden, who performed the first laparoscopic intervention in 1901 using a Nitze cystoscope in a dog. In 1910 Jacobaeus published his first experiences with laparoscopic surgery in the Münchner Medizinische Wochenschrift under the title "The possibility to perform cystoscopy in examinations of serous cavities." He used this technique for diagnostic purposes in unclear abdominal complaints and functional impairment. Jacobaeus was the first who pointed out the possibility of causing injury to organs, especially the gut, by inserting the trocar. In 1910 Jacobaeus recognized the immense diagnostic and therapeutic possibilities of laparoscopic surgery, but also the difficulties and limits. He also was the first who recognized the need to complete training sessions on animals and corpses. He demanded the development of special laparoscopic instruments to optimize and simplify the operation.

Due to its efficiency and low capital demands, chlorination has been widely used for disinfection in many wastewater treatment plants. Since the oxidation power of free chlorine is bigger than combined chlorines which are formed from the reaction between chlorine and reducing agents in water (especially, NH4+ and organic nitrogen), for effective disinfection, excess amount of chlorine is added until all the reducing agents are oxidized and free chlorine is available. After chlorination, chlorine residues in wastewater are usually reduced with SO2 or sulfites before the treated wastewater is discharged, since they are toxic to aquatic life. Addition of excess amount of SO2 or sulfite should be avoided. Otherwise, they consume dissolved oxygen in a river or stream and may have adverse impact on the aquatic life. Determination of wastewater chlorine demand and of sulfite dosages for dechlorination has been a challenge to WWTP operators, due to the dynamic characteristics of wastewater. Recently, a new ORP/pH based approach to determine chlorine demand and sulfite dosage was proposed. The method utilizes significant points occurring on the pH and ORP profiles during chlorination and dechlorination titrations. In this study, the proposed automatic titration system has been implemented into a control system to optimize chlorine and sulfite doses for a pilot scale chlorination/dechlorination system. In short, the disinfection system with the pH/ORP based controller showed very successful results; complete inactivation of total coliforms, and almost zero residual chlorines and high DO in its effluent.

Due to its efficiency and relatively low capital demanding, many wastewater treatment plants have applied chlorination for disinfection of treated wastewater before discharging it. However, determination of optimal doses of chlorine for chlorination and sulfite for dechlorination, which removes residual chlorine, should made to guarantee complete destruction of microorganisms in treated wastewater and to protect aquatic life in a receiving stream. In this study, a new ORP/pH based approach to determine endpoints of breakpoint chlorination and of dechlorinating titration and to optimize doses of chlorine and sulfite. In this new method, significant points on the ORP and pH profiles occurring during the titrations for chlorination and dechlorination were utilized to determine chlorine demand and sulfite dosage.

Large number density Pt nanowires with typical dimensions of 12 microm x 20 nm x 5 nm (length x width x height) are fabricated on planar oxide supports. First sub-20 nm single crystalline silicon nanowires are fabricated by size reduction lithography, and then the Si nanowire pattern is replicated to produce a large number of Pt nanowires by nanoimprint lithography. The width and height of the Pt nanowires are uniform and are controlled with nanometer precision. The nanowire number density is 4 x 10(4) cm(-1), resulting in a Pt surface area larger than 2 cm(2) on a 5 x 5 cm(2) oxide substrate. Bimodal nanowires with different width have been generated by using a Pt shadow deposition technique. Using this technique, alternating 10 and 19 nm wide nanowires are produced.

Chemical and morphological heterogeneities of carbon sorbents play important roles in gas-phase adsorption. However, the specific chemical complexes and topological structures of carbon that favor or impede elemental mercury uptake are not well understood and are the subject of this study. Temperature programmed desorption (TPD) with a model carbonaceous material (highly oriented pyrolytic graphite, HOPG) under ultrahigh vacuum (UHV) conditions and fixed bed adsorption by activated carbon (BPL) at atmospheric pressure were combined to investigate the effects of chemical and morphological heterogeneities on mercury adsorption by carbonaceous surfaces. TPD results show that mercury adsorption at 100 K onto HOPG surfaces with and without chemical functional groups and topological heterogeneity created by plasma oxidation occurs through physisorption. The removal of chemical functionalities from the HOPG surface enhances mercury physisorption. Plasma-oxidation of HOPG provides additional surface area for mercury adsorption. However, the pits created by plasma oxidation are more than 10 nm in diameter and do not simulate microporosity that predominates in activated carbons. Mercury adsorption by activated carbon at atmospheric pressure occurs through two distinct mechanisms. Physisorption governs mercury adsorption at lower temperatures (i.e., below 348 K), while chemisorption predominates at high adsorption temperatures (i.e., above 348 K). Presence of water on activated carbon surface enhances mercury uptake by both physisorption and chemisorption. Oxygen containing functional groups reduce mercury uptake by physisorption by blocking access to the micropores. No significant impact of oxygen functionalities was observed in the chemisorption regime. The key findings of this study open the possibility to apply scientific information obtained from the studies with simple surfaces such as HOPG under ideal conditions (UHV) to industrial sorbents under realistic process conditions.

Nitric oxide (NO) derived from inducible NO synthase (iNOS) at sites of inflammation is closely related to host defense against infection and airway inflammation. Cytokines are known to stimulate NO production in human alveolar epithelial cells in a synergistic (nonlinear or nonadditive) manner. The mechanism of this synergy is not known. We measured the activation of the transcription factor NF-kappaB, the iNOS protein, and NO production in A549 monolayers (human alveolar epithelial cell line) in response to different combinations of IL-1beta, INF-gamma, and TNF-alpha (100 ng/ml), and the cofactors FMN, FAD, and BH4. We found that both IL-1beta and TNF-alpha could independently activate cytosolic NF-kappaB, direct its translocation into the nucleus, and induce iNOS monomer synthesis. In addition, different combinations of cytokines produced synergistic amounts of iNOS monomers. Exogenous BH4 (0.1 microM) had no impact on NO production induced by cytokine combinations that included IL-1beta, but significantly enhanced NO production in the presence of INF-gamma and TNF-alpha, and allowed TNF-alpha independently to produce NO. We conclude that there are at least three mechanisms of synergistic cytokine-induced NO production: (1) the biosynthesis of iNOS monomer due to nonlinear interactions by transcription factors, (2) synergistic cytosolic activation of NF-kappaB, and (3) parallel biosynthesis of BH4 in the presence of cytokine combinations that include IL-1beta.

Effects of clonidine, an imidazoline derivative as well as alpha2-adrenoceptor agonist, on carbachol (CCh)-evoked contraction in guinea pig ileal smooth muscle were studied using isometric tension recording. To investigate the cellular mechanisms of the inhibitory effect of clonidine, its effects on CCh-evoked nonselective cationic current (I(CCh)), voltage-dependent Ca2+ current (I(Ca)) and voltage-dependent K+ current (I(K)) was also studied using patch-clamp recording techniques in single ileal cells. Clonidine inhibited the contraction evoked by CCh (1 microM) in a concentration-dependent manner with an IC50 valve of 61.7 +/- 2.5 microM. High K+ (40 mM)-evoked contraction was only slightly inhibited even when clonidine was used at 300 microM. Externally applied clonidine inhibited I(CCh) dose-dependently with an IC50 of 42.0 +/- 2.6 microM. When applied internally via patch pipettes, clonidine was without effect. An I(CCh)-like current induced by GTPgammaS was also inhibited by bath application of clonidine. None of KU14R and BU224, both imidazoline receptor blockers, and yohimbine, an alpha2-adrenergic blocker, significantly affects the inhibitory effect of clonidine on I(CCh). Clonidine (300 microM) only slightly decreased membrane currents flowing through voltage-gated Ca2+ channels or K+ channels. These data indicate that clonidine relaxes smooth muscle contraction produced by muscarinic receptor activation and suggest that the effect of clonidine seems due mainly to inhibition of I(CCh) via acting directly on the involved cationic channel.

The nematode Caenorhabditis elegans has many advantages for studying gene function at the organism level. In particular, completion of the genome sequencing has made it feasible to study gene structure and function of both known and novel proteins. As a result of a database search for muscle-specific genes, a gene F43D9.1 was found which showed muscle-specific expression as revealed by the in situ hybridization pattern from the Expressed Sequence Tag (EST) database. A homology search of F43D9.1 protein sequences showed no significant homology with other known proteins, except that it showed very weak sequence similarity with the band 4.1 protein superfamily. Northern blot analysis reveals a single transcript 3.7 kb in size which is consistent with the predicted gene structure. The expression pattern of F43D9.1 was investigated using the gfp reporter gene, and it has shown to be expressed in neuronal cells including sensory neurons and interneurons in the head region. To further characterize F43D9.1, whole-mount immunostaining was performed with anti-F43D9.1 antibody, which showed specific signals in head neurons, body-wall muscle cells, some other unidentified neuronal cells, and centrosomes of the dividing cells during embryogenesis. Taken together with its predicted membrane topology, we speculate that the F43D9.1 gene, which encodes a novel transmembrane protein and contains a band 4.1-like domain, may function in neuromuscular cells, and may play an important role during cell division in C. elegans., (Copyright 2001 John Wiley & Sons, Ltd.)

In the present study mechanism of inhibitory effects of capsaicin on the contractility of rabbit coronary artery were studied by measurement of isometric tension and intracellular Ca2+ concentration. Capsaicin (1 microM to 30 microM) relaxed the coronary artery pre-contracted with prostaglandin (PG) F2alpha (1 microM) in a concentration-dependent manner. The PGF2alpha-induced increase in intracellular Ca2+ concentration was also inhibited. The effects of capsaicin were readily reversed by washing capsaicin from the bath. Capsaicin-induced relaxation was not attenuated by pretreatment with capsazepine (1 microM), a blocker of vanilloid receptor or ruthenium red (1 microM), a blocker of non-selective cation channel. Previous exposure to a high concentration of capsaicin (100 microM) or repeated application of capsaicin did not eliminate the relaxation response to subsequent application of capsaicin. Increasing the external K+ concentration to 80 mM significantly attenuated the capsaicin-induced relaxation with simultaneous change in intracellular Ca2+ concentration. Pretreatment with iberiotoxin (100 nM), a blocker of Ca2+-activated K+ channel, only partially inhibited the capsaicin-induced relaxation. However, application of 4-aminopyridine (4-AP, 1 mM), a blocker of delayed rectifier K+ current significantly inhibited the capsaicin-induced relaxation with concomitant attenuation of the effect on intracellular Ca2+ concentration. These results indicate that capsaicin may have a direct relaxing effect on the smooth muscle contractility, and relaxation may be due to activation of the 4-AP-sensitive, delayed rectifier K+ channels in the rabbit coronary artery.

This study was performed to examine the antinociceptive effect after microinjection of arginine vasopressin (AVP) into the central nucleus of amygdala. We recorded the jaw opening reflex in freely moving rats. After injection of 0.2 or 0.4 nM AVP into the central nucleus of amygdala, digastric electromyogram (dEMG) was suppressed to 55 +/- 5% or 88 +/- 3 of the control. Artificial cerebrospinal fluid had no effects on the basal dEMG activity. V(1) vasopressin receptor antagonist blocked the suppressive effect produced by microinjection of 0.4 nM AVP from 53 +/- 3 to 81 +/- 3% of the control. However, V(2) vasopressin receptor antagonist did not affect changes in dEMG. We observed dEMG activity after intracerebroventricular injection of naloxone, methysergide, or phentolamine. All drugs did not affect the basal dEMG activity at our dose. Naloxone blocked the suppressive effect of 0.4 nM AVP from 42 +/- 4 to 79 +/- 5% of the control. Methysergide also inhibited the suppression of dEMG from 44 +/- 3 to 83 +/- 6% of the control. However, phentolamine, an alpha-adrenergic receptor antagonist, did not affect the suppression of dEMG. These results indicate AVP in the central nucleus of amygdala has potent analgesic effects in the orofacial area. The antinociception of central AVP seems to be mediated by opioid and serotonergic pathways.

Reversible posterior leukoencephalopathy syndrome is a recently recognized disorder with characteristic radiologic findings that mainly involve the white/gray matter of the parieto-occipital lobes. This complex syndrome is associated with cyclosporine A therapy or a variety of other conditions in which blood pressure rises acutely. Twelve patients from a variety of conditions who met the diagnostic criteria for this syndrome were studied. Interestingly, three of these patients had intra-abdominal neurogenic tumors, which have rarely been reported. Initial cranial magnetic resonance imaging scans revealed fairly symmetric areas of increased T(2) signal involving both white and gray matter of parieto-occipital lobes in the majority of the patients. However, the lesions were often located outside the parieto-occipital regions. Four patients had occipital region magnetic resonance spectroscopy during the acute phase, which revealed high lactate peak and normal N-acetyl aspartate/creatine and choline peaks. With appropriate treatment, most patients recovered from this syndrome and experienced almost complete resolution of brain lesions on follow-up magnetic resonance imaging. One patient, however, continued to have small residual hemosiderin deposits on a follow-up magnetic resonance imaging with neurologic sequellae. In conclusion, a better understanding of this complex syndrome may obviate unnecessary investigations and allow management of the associated problems in prompt and appropriate ways.

It is important to produce L(+)-lactic acid at the lowest cost possible for lactic acid to become a candidate monomer material for promising biodegradable polylactic acid. In an effort to develop a high-rate bioreactor that provides high productivity along with a high concentration of lactic acid, the performance of membrane cell-recycle bioreactor (MCRB) was investigated via experimental studies and simulation optimization. Due to greatly increased cell density, high lactic acid productivity, 21.6 g L(-1) h(-1), was obtained in the reactor. The lactic acid concentration, however, could not be increased higher than 83 g/L. When an additional continuous stirred tank reactor (CSTR) was attached next to the MCRB a higher lactic acid concentration of 87 g/L was produced at significant productivity expense. When the two MCRBs were connected in series, 92 g/L lactic acid could be produced with a productivity of 57 g L(-1) h(-1), the highest productivity among the reports of L(+)-lactic acid that obtained lactic acid concentration higher than 85 g/L using glucose substrate. Additionally, the investigation of lactic acid fermentation kinetics resulted in a successful model that represents the characteristics of lactic acid fermentation by Lactobacillus rhamnosus. The model was found to be applicable to most of the existing data with MCRBs and was in good agreement with Levenspiel's product-inhibition model, and the Luedeking-Piret equation for product-formation kinetics appeared to be effective in representing the fermentation kinetics. There was a distinctive difference in the production potential of cells (cell-density-related parameter in Luedeking-Piret equation) as lactic acid concentration increases over 55 g/L, and this finding led to a more precise estimation of bioreactor performance., (Copyright 2001 John Wiley & Sons, Inc.)