Comparison of regional with general anaesthesia on postoperative delirium (RAGA-delirium) in the older patients undergoing hip fracture surgery: study protocol for a multicentre randomised controlled trial.
Postoperative delirium (POD) is a common serious postoperative complication especially in older people and is associated with increased mortality, morbidity and healthcare costs. There is no clear consensus which anaesthesia is associated with less incidence of POD for older patients. We aim to assess whether regional anaesthesia results in lower incidence of POD comparing with general anaesthesia (GA) among older patients undergoing hip fracture surgery. RAGA-delirium is a pragmatic, multicentre, prospective, parallel grouped, randomised controlled clinical trial comparing RA or GA for hip fracture surgery. A total of 1000 patients who are 65 years or over and who are having planned hip fracture surgery in nine clinical trial centres of China will be randomised in a 1:1 ratio to receive either anaesthesia for the surgery. The primary endpoint will be the incidence of POD at day 7. The secondary endpoints will be the subtype, severity and duration of delirium, postoperative acute pain score, incidence of other postoperative non-delirium complications, quality of life and cost-effective outcomes. Randomisation will be performed at the patient level using computer-generated assignment. Outcome assessors will be blinded from intervention assignment. Assessments will be conducted before surgery, intraoperatively, postoperatively, during the hospital stay, at 30-day, 6-month and 1-year postoperative intervals. This study will provide clinical evidence with a more robust methodology to help anaesthetists in selecting appropriate anaesthesia for older patients with high risk for POD. At the era of increasing emphasis on delirium prevention, this trial has the potential to inform the future national guideline to reduce POD. Ethical approved by the local institutional review board. Trial results will be presented at national and international academic conferences, and published in peer-reviewed journals. ClinicalTrials.gov (NCT02213380); pre-results.


Effects of Turmeric Concentrate on Cardiovascular Risk Factors and Exercise-Induced Oxidative Stress in Healthy Volunteers; an Exploratory Study.
Evidence suggests that turmeric intake can improve antioxidant defense, blood pressure (BP), ageing and gut microbiota. The effects of turmeric concentrate (curcumin) intake on cardiovascular risk factors and exercise induced oxidative stress were investigated. A randomized placebo-controlled study was performed to assess the effects of turmeric extract in healthy volunteers before and after a 30 min exercise bout. Participants (n=22) were given either turmeric concentrate or placebo supplements. Anthropometry, BP, pulse wave velocity (PWV), biomarkers of oxidative stress, perceived exertion and lipid peroxidation were assessed. In the turmeric group, the expected BP response to exercise following turmeric was blunted and the increase was not significant compared to basal values followed by a decrease in final BP and PWV values. There were no significant differences in all baseline parameters between the placebo and the curcumin groups (P>0.05). A significant increase was observed in urinary antioxidant power (P=0.031) and total polyphenol levels (P=0.022) post turmeric intervention. The distance ran by the participants taking turmeric was significantly longer (P=0.005) compared to basal value. Those who took the placebo did not show significant changes. Our study suggests that turmeric concentrate intake can reduce BP and improve antioxidant, anti-inflammatory status and arterial compliance. Turmeric may improve exercise performance and ameliorates oxidative stress. Larger studies are warranted to validate these findings and test more cardiovascular risk factors.


Purification and characterization of novel chondroitin ABC and AC lyases from Bacteroides stercoris HJ-15, a human intestinal anaerobic bacterium.
Two novel chondroitinases, chondroitin ABC lyase (EC 126.96.36.199) and chondroitin AC lyase (EC 220.127.116.11), have been purified from Bacteroides stercoris HJ-15, which was isolated from human intestinal bacteria with glycosaminoglycan degrading enzymes. Chondroitin ABC lyase was purified to apparent homogeneity by a combination of QAE-cellulose, CM-Sephadex C-50, hydroxyapatite and Sephacryl S-300 column chromatography with a final specific activity of 45.7 micromol.min-1.mg-1. Chondroitin AC lyase was purified to apparent homogeneity by a combination of QAE-cellulose, CM-Sephadex C-50, hydroxyapatite and phosphocellulose column chromatography with a final specific activity of 57.03 micromol.min-1.mg-1. Chondroitin ABC lyase is a single subunit of 116 kDa by SDS/PAGE and gel filtration. Chondroitin AC lyase is composed of two identical subunits of 84 kDa by SDS/PAGE and gel filtration. Chondroitin ABC and AC lyases showed optimal activity at pH 7.0 and 40 degrees C, and 5.7-6.0 and 45-50 degrees C, respectively. Both chondroitin lyases were potently inhibited by Cu2+, Zn2+, and p-chloromercuriphenyl sulfonic acid. The purified Bacteroidal chondroitin ABC lyase acted to the greatest extent on chondroitin sulfate A (chondroitin 4-sulfate), to a lesser extent on chondroitin sulfate B (dermatan sulfate) and C (chondroitin 6-sulfate). The purified chondroitin AC lyase acted to the greatest extent on chondroitin sulfate A, and to a lesser extent on chondroitin C and hyaluronic acid. They did not act on heparin and heparan sulfate. These findings suggest that the biochemical properties of these purified chondroitin lyases are different from those of the previously purified chondroitin lyases.


Migration and vascular lumen formation of endothelial cells in cancer cell spheroids of various sizes.
We developed a microfluidic device to culture cellular spheroids of controlled sizes and suitable for live cell imaging by selective plane illumination microscopy (SPIM). We cocultured human umbilical vein endothelial cells (HUVECs) within the spheroids formed by hepatocellular carcinoma cells, and studied the distributions of the HUVECs over time. We observed that the migration of HUVECs depended on the size of spheroids. In the spheroids of ∼200 μm diameters, HUVECs migrated outwards to the edges within 48 h; while in the spheroids of ∼250 μm diameters, there was no outward migration of the HUVECs up to 72 h. In addition, we studied the effects of pro-angiogenic factors, namely, vascular endothelial growth factor (VEGF) and fibroblast growth factor (β-FGF), on the migration of HUVECs in the carcinoma cell spheroid. The outward migration of HUVECs in 200 μm spheroids was hindered by the treatment with VEGF and β-FGF. Moreover, some of the HUVECs formed hollow lumen within 72 h under VEGF and β-FGF treatment. The combination of SPIM and microfluidic devices gives high resolution in both spatial and temporal domains. The observation of HUVECs in spheroids provides us insight on tumor vascularization, an ideal disease model for drug screening and fundamental studies.


Updating small area population estimates in England and Wales.
"Population estimates have important implications for resource allocation within government and commerce, and are often assumed to be without error. Currently, central government provides annual population estimates for all the local and health authority districts in Britain, but estimates are needed for smaller areas, typically for electoral wards and postal sectors. Small area estimates are provided by some local authorities and commercial organizations, using different methods; the accuracy of these estimates is modelled here within a multilevel framework. Certain characteristics of the small area and of the method of estimation are included as explanatory variables. Results show that the method of estimation used is of great importance."


Palladium membrane-installed microchannel devices for instantaneous Suzuki-Miyaura cross-coupling.
Instantaneous catalytic carbon-carbon bond-forming reactions were achieved in catalytic membrane-installed microchannel devices that have a polymeric palladium-complex membrane. The catalytic membrane-installed microchannel devices were provided inside the microchannels by means of coordinative and ionic molecular convolution at the interface between the organic and aqueous phases flowing laminarly, in which both non-crosslinked linear polymer ligands and palladium species dissolved. The palladium-catalyzed Suzuki-Miyaura reaction of aryl, heteroaryl, and alkenyl halides with arylboronic acids and sodium tetraarylborates was performed with the catalytic membrane-installed microchannel devices to give quantitative yields of biaryls, heterobiaryls, and aryl alkenes within 5 s of residence time in the defined channel region. These microchannel devices were applied to the instantaneous allylic arylation reaction of allylic esters with arylboron reagents under microflow conditions to afford the corresponding coupling products within 1 s of residence time.


Investigation of soy protein hydrogels for biomedical applications: materials characterization, drug release, and biocompatibility.
Soy protein is emerging as a novel material for biomedical applications due to its abundance in nature, ease of isolation and processing, and inherent properties for mediating cell adhesion and growth. In this study, mechanically robust soy protein hydrogels were fabricated with varying weight percentages in water (15, 18, and 20 wt.%) without the use of chemical modifiers or crosslinkers. This fabrication method is beneficial because it allows for the direct injection of these soy hydrogels in vivo. The material properties, drug releasing capability, and biocompatibility in vitro and in vivo were assessed. The different concentrations of soy protein varied the rheological, swelling, and mechanical properties and affected the release of the model drug fluorescein from the hydrogels in vitro. Higher weight percent of soy increased the robustness of the hydrogels and released a lower amount of fluorescein over one week. Viability and growth of seeded L929 mouse fibroblasts demonstrated that the hydrogels were biocompatible in vitro for one week. Soy hydrogels were injectable in vivo into the subcutaneous pocket of mice, and histological staining showed minimal fibrous capsule formation for up to 20 days. The ease of fabrication and tailorable properties of soy hydrogels render it a promising biomaterial for tissue engineering and drug delivery applications, particularly for wound healing.


The morphologic correlation between vortex transformation and upper critical field line in opal-based nanocomposites.
In this study, we investigate metallic nanocomposites to elucidate the properties of nanostructured conventional superconductors. Liquid tin, indium, and mercury are loaded into opal matrices by high pressure up to 10 kbar. The opal templates preserve the 3D dendritic morphology of confined superconducting metals to model a dendritic second phase with particular grain shape in bulk superconductors observed by a DualBeam microscope. We carry out measurements of the dc and ac magnetizations to study the superconducting phase diagrams, vortex dynamics, and impact of grain morphology in the opal composites. Besides, we apply the small-angle neutron scattering (SANS) to deny a regular vortex structure. The phase diagrams reveal an enhanced upper critical field Hc2(0) and curvature crossover in the upper critical field line. We also calculate the vortex activation barriers Ua and observe a transformation in the vortex system. According to the field dependence of Ua, the vortex structure transformation highly correlates with the curvature crossover in the upper critical field line. Our observations suggest that the similarity in the normalized phase diagrams and field dependences of Ua in the three nanocomposites is owing to their particular morphology of confinement.


Identifying Optimal Zeolitic Sorbents for Sweetening of Highly Sour Natural Gas.
Raw natural gas is a complex mixture comprising methane, ethane, other hydrocarbons, hydrogen sulfide, carbon dioxide, nitrogen, and water. For sour gas fields, selective and energy-efficient removal of H2 S is one of the crucial challenges facing the natural-gas industry. Separation using nanoporous materials, such as zeolites, can be an alternative to energy-intensive amine-based absorption processes. Herein, the adsorption of binary H2 S/CH4 and H2 S/C2 H6 mixtures in the all-silica forms of 386 zeolitic frameworks is investigated using Monte Carlo simulations. Adsorption of a five-component mixture is utilized to evaluate the performance of the 16 most promising materials under close-to-real conditions. It is found that depending on the fractions of CH4 , C2 H6 , and CO2 , different sorbents allow for optimal H2 S removal and hydrocarbon recovery.


Management of Femur and Tibial Leg Length Discrepancies With a Unilateral External Fixator Is Still Viable When More Advanced Techniques and Hardware Are Unavailable or Cost-Prohibitive.
Introduction Leg length discrepancy (LLD) is an infrequent diagnosis, most commonly occurring congenitally in children and rarely in traumatic incidents in adults. Circumferential external fixators are considered the optimal treatment method, but can be very costly and are not always readily available in less developed nations. The unilateral external fixator predates the circumferential but is more easily available and accessible worldwide and less expensive. This study sought primarily to characterize treatment outcomes using a unilateral external fixator where more advanced forms of treatment for LLD are not available. Secondary objectives included the site of the discrepancy and comparison of etiologies. Methods Data were retrospectively reviewed from January 2010 to December 2017 on patients undergoing unilateral external fixation at our institution. Nineteen patients met the criteria, 14 with congenital LLD and five with lower leg bone loss from trauma. Patient demographics (including gender and age), initial presentation, physical examination findings, radiographic findings, and treatment were collected and saved in an electronic medical record. Results There were 19 cases of LLD overall, with 14 cases on the tibia and 5 on the femur. Three of the five femur cases occurred in the trauma subgroup. There were 15 cases of congenital LLD and five cases of traumatic LLD. The mean overall LLD was 3.9 cm (2.3-5.2). The mean follow-up until healing for the entire cohort was 10 months (5-22). Patients with congenital LLD were younger than those with traumatic LLD (10.2 years versus 22.5 years, p=0.000013), more likely to have a tibial discrepancy (p=0.034), and had a shorter time frame until full healing (7.6 months versus 19 months, p 0.00001). Patients with a tibial LLD were more likely to have a congenital etiology (p=0.0374) and had a shorter time until full healing compared to patients with a femur LLD (8.5 months versus 14 months, p=0.03541). Conclusion We conclude that bone lengthening utilizing the unilateral external fixator is a good method and is cost-effective for bone lengthening where more advanced techniques are not available or cost-prohibitive. It is simple, and patients and families can collaborate with the surgeon to get a good final result. Patients are generally satisfied and can ambulate well after healing. In a resource-limited environment with cost as a barrier, if used correctly and judiciously, the unilateral external fixator can yield good results.


CYP2C19 polymorphisms and antiplatelet effects of clopidogrel in acute ischemic stroke in China.
Little research regarding genotypes and clopidogrel response related to acute ischemic stroke has been published. This study was conducted to investigate whether the polymorphisms of receptors or enzymes involved in the metabolic process of clopidogrel affect clopidogrel response and prognosis related to acute stroke. A total of 259 patients with acute ischemic stroke were enrolled in this study; all received follow-up evaluations 3 and 6 months after clopidogrel treatment. CYP2C19, CYP3A4, and P2Y12 were screened. The adenosine diphosphate-induced platelet aggregation test, the National Institutes of Health Stroke Scale (NIHSS), and the modified Rankin Scale (mRS) were used, and blood vascular events were evaluated. The difference before and after clopidogrel treatment on adenosine diphosphate-induced platelet aggregation was significantly smaller in patients carrying 1 or 2 CYP2C19 loss-of-function alleles (*2, *3) compared with patients carrying none. Patients with none had better outcomes than patients with CYP2C19 loss-of-function alleles, as demonstrated by NIHSS and mRS scores at 3 and 6 months after treatment. Regression analysis showed that CYP2C19 was an independent predictor of clopidogrel resistance. CYP2C19 genotypes had significant impact on clopidogrel response and prognosis of patients with stroke. Clinical Trial Registration Information- URL: http://www.chictr.org/. Unique Identifier: ChiCTR-OCH-12002681.


Unproven methods of cancer management. Laetrile.
"Laetrile" is used interchangeably with "amygdalin" to designate natural substances, derived primarily from apricots and almonds, that can release cyanide, which is lethal to living organisms. In the 1920s, Dr. Ernst T. Krebs, Sr., formulated a theory that amygdalin could kill cancer cells. His theory was inconsistent with biochemical facts and has since been modified at least twice by his son, Ernst T. Krebs, Jr. Extensive work has been done by cancer scientists to test the claim that Laetrile fights cancer. Many animal experiments in the 1970s showed a complete lack of tumor killing by Laetrile. Reviews of the medical records of patients whose cancers were claimed to be reduced or cured after Laetrile treatment found insufficient medical evidence to judge Laetrile's efficacy. Finally, in a clinical trial in cancer patients reported in 1982, Laetrile neither caused shrinkage of tumors, nor increased survival time, nor alleviated cancer symptoms, nor enhanced well-being. Several reports in the medical literature document instances in which Laetrile has caused serious, life-threatening toxicity when taken in large doses in the manner prescribed by Laetrile advocates. In light of the lack of efficacy of Laetrile and its demonstrated ability to cause harm, Laetrile should not be used to treat cancer.


[The recent evolution of fertility in Quebec: demographic and socioeconomic determinants].
The purpose of this study is to assess the factors which have influenced the evolution of fertility in Quebec between 1960 and 1990, in order to have a better focus on short and middle term fertility's determining factors. A Whittaker-Henderson filter is applied to various variables presumably linked to the total fertility index in order to retrieve and isolate the trend, which then enables concentration on residuals' co-variations. A regression analysis then enables assessment of the factors' weights and the short term's influence (business cycle). Governmental incentives, notably between 1988 and 1990, appear as having contributed, as well as the overall economic conjuncture, to the observed total fertility index raise in the course of this period.


Characterization of a descending pathway: activation and effects on motor patterns in the brachyuran crustacean stomatogastric nervous system.
The regulation of motor patterns by higher-order neuronal centers ensures appropriate motor function and behavior, but only a few studies have characterized this regulation at the cellular level. Here, we address motor pattern regulation in the stomatogastric nervous system (STNS) of the crab Cancer pagurus. This easily accessible model system is an extension of the central nervous system and contains the motor circuits that generate the rhythmic motor patterns for ingestion (esophageal rhythm) and processing of food (gastric mill and pyloric rhythms). We have documented the actions of two identified neurons located in the brain on the STNS motor circuits. We show that these neurons provide exteroceptive chemosensory information to the motor circuits and we outline their axonal projection patterns, their firing activity and their effects on three motor patterns. Backfill stainings and activity measurements in vivo and in vitro show that two neurons located in cluster 17 of the brain project via the inferior ventricular (IV) nerve to the STNS. These IV neurons started to burst rhythmically when chemosensory stimuli were applied to the first antennae. When rhythmically activated in vitro, gastric mill rhythms were elicited or, if already active, entrained by the IV neuron activity. In addition, IV neuron stimulation excited the esophageal motor neuron and inhibited several pyloric neurons such that the timing of the IV neuron activity was imposed on all motor rhythms. The IV neurons were thus capable of synchronizing the activities of different motor circuits, which demonstrates the regulation of motor patterns by higher-order neuronal centers.


In vitro inhibition of murine macrophage migration by Bordetella pertussis lymphocytosis-promoting factor.
Lymphocytosis promoting factor (LPF) of Bordetella pertussis is a protein toxin which may have a role in the pathogenesis of pertussis. Since macrophages have an important role in the control of respiratory infections, the in vitro effects of LPF on macrophages from C3H/HeN and C3H/HeJ mice and on a murine macrophage-like cell line, RAW264, were examined. LPF inhibited random migration of resident peritoneal macrophages as well as the chemotaxis of peritoneal macrophages and the cell line. Fifty percent inhibition of chemotaxis occurred at 0.2 to 0.3 ng of LPF per ml for the macrophages and at 1 to 2 ng of LPF per ml for the cell line. When LPF was either heated at 80 degrees C for 5 min or premixed with specific antibodies, it failed to inhibit migration. At 20 ng/ml, LPF inhibited chemotaxis by more than 80% and also decreased Fc-mediated phagocytosis by 25 to 35%. At this dose, LPF was not a chemoattractant for murine macrophages and did not reduce macrophage viability, adherence, or opsonized zymosan-stimulated superoxide release. When LPF-treated macrophages were added to tissue culture dishes and then examined microscopically after 4 h, the LPF-treated cells adhered but failed to spread and elongate as well as control macrophages. These data indicate that LPF specifically inhibits macrophage migration in vitro and suggest that a possible role for LPF in pathogenesis is to inhibit migration of macrophages to the site of B. pertussis infection.


The developmental bases of limb reduction and body elongation in squamates.
Employing an integrative approach to investigate the evolution of morphology can yield novel perspectives not attainable from a single field of study. Studies of limb loss and body elongation in squamates (snakes and lizards) present a good example in which integrating studies of systematics and ecology with genetics and development can provide considerable new insight. In this comment we address several misunderstandings of the developmental genetic literature presented in a paper by Wiens and Slingluff (2001) to counter their criticism of previous work in these disciplines and to clarify the apparently contradictory data from different fields of study. Specifically, we comment on (1) the developmental mechanisms underlying axial regionalization, body elongation, and limb loss; (2) the utility of presacral vertebral counts versus more specific partitioning of the primary body axis; (3) the independent, modular nature of limbs and limb girdles and their utility in diagnosing genetic changes in development; and (4) the causal bases of hind limb reduction in ophidian and nonophidian squamates.


Gradient-band-gap strategy for efficient solid-state PbS quantum-dot sensitized solar cells.
To improve charge separation and enhance open-circuit voltage (Voc) in solid-state quantum-dot sensitized solar cells (QDSCs), gradient-band-gap PbS quantum-dots were first and easily constructed by two-step spin-coating the Pb(NO3)2 solution and the mixed solution of Na2S and 1,2-ethanedithiol via successive ionic layer absorption and reaction (SILAR). The fabricated solid-state gradient-band-gap PbS QDSCs exhibited a Voc of 0.70 V, a short-circuit photocurrent density (Jsc) of 9.65 mA·cm-2, a fill factor (FF) of 0.60, and a photoelectric conversion efficiency (PCE) of 4.08%, while the inverse gradient-band-gap PbS QDSCs showed a Voc of 0.59 V, a Jsc of 5.86 mA·cm-2, an FF of 0.49 and a PCE of 1.69%. By optimization, the best solid-state gradient-band-gap PbS QDSCs achieved a Voc of 0.65 V and a PCE of 6.29% under 1 sun, and a Voc of 0.60 V and a PCE of 7.21% under 0.5 sun. The Voc of 0.65 V was relatively high, and the PCE of 6.29% was the highest value among solid-state QDSCs constructed using SILAR.


Direct repression of FLIP expression by c-myc is a major determinant of TRAIL sensitivity.
Tumor necrosis factor alpha (TNF-alpha)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF-alpha family of death receptor ligands and holds great therapeutic potential as a tumor cell-specific cytotoxic agent. Using a panel of established tumor cell lines and normal cells, we found a significant difference between the number of TRAIL-sensitive cells expressing high levels of c-myc and TRAIL-resistant cells expressing low levels of c-myc (P < 0.05, n = 19). We also found a direct linear correlation between c-myc levels and TRAIL sensitivity in TRAIL-sensitive cell lines (r = 0.94, n = 6). Overexpression of c-myc or activation of a myc-estrogen receptor (ER) fusion sensitized TRAIL-resistant cells to TRAIL. Conversely, small interfering RNA (siRNA)-mediated knockdown of c-myc significantly reduced both c-myc expression and TRAIL-induced apoptosis. The gene encoding the inhibitor of caspase activation, FLICE inhibitory protein (FLIP), appears to be a direct target of c-myc-mediated transcriptional repression. Overexpression of c-myc or activation of myc-estrogen receptor (ER) decreased FLIP levels both in cell culture and in mouse models of c-myc-induced tumorigenesis, while knocking down c-myc using siRNA increased FLIP expression. Chromatin immunoprecipitation and luciferase reporter analyses showed that c-myc binds and represses the human FLIP promoter. c-myc expression enhanced TRAIL-induced caspase 8 cleavage and FLIP cleavage at the death-inducing signaling complex. Combined siRNA-mediated knockdown of FLIP and c-myc resensitized cells to TRAIL. Therefore, c-myc down-regulation of FLIP expression provides a universal mechanism to explain the ability of c-myc to sensitize cells to death receptor stimuli. In addition, identification of c-myc as a major determinant of TRAIL sensitivity provides a potentially important screening tool for identification of TRAIL-sensitive tumors.


Molecular targeting of growth factor receptor-bound 2 (Grb2) as an anti-cancer strategy.
Growth factor receptor-bound 2 (Grb2) is a ubiquitously expressed adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. As such, it has been implicated in the oncogenesis of several important human malignancies. In addition to this function, research over the last decade has revealed other fundamental roles for Grb2 in cell motility and angiogenesis--processes that also contribute to tumor growth, invasiveness and metastasis. This functional profile makes Grb2 a high priority target for anti-cancer drug development. Knowledge of Grb2 protein structure, its component Src homology domains and their respective structure-function relationships has facilitated the rapid development of sophisticated drug candidates that can penetrate cells, bind Grb2 with high affinity and potently antagonize Grb2 signaling. These novel compounds offer considerable promise in our growing arsenal of rationally designed anti-cancer therapeutics.


Is breast MRI ever useful in a mammographic screening programme?
To establish the diagnostic impact of breast magnetic resonance imaging (MRI), on the management of cases in our mammographic screening programme. We analysed the cases examined from July 1997 to December 2000 during which time 44,000 population screening mammograms and 85 MRI studies were undertaken on women identified by computer overlap. The studies were reviewed to find the reason for the MRI study and its diagnostic impact. Of 83 studies analysed, 31 were for recurrence of tumour, 33 in newly diagnosed cancer, 22 to assess extent, 11 to monitor primary chemotherapy. In a small diagnostic subset of 19 cases MRI was used to find or characterize a lesion. The 11 cases in which MRI results caused a measurable beneficial change in management were from the query recurrence and diagnostic groups. In 52 cases from all groups, MR increased diagnostic confidence. In 11 cases MRI results were indeterminate, and in six of these stimulated more studies. MRI is an expensive investigation and its use must be justified. There is a limited, but valuable role for breast MRI in selected cases from screening assessment. Misinterpretation of enhancing lesions may generate additional procedures. Diagnostic impact was greatest for the detection of tumour recurrence.


Non-lactate strong ion difference and cardiovascular, cancer and all-cause mortality.
Non-lactate strong ion difference (SID) has been shown to be associated with predictors of mortality in intensive care unit. However, the existence of any association between non-lactate SID (nlSID) and all cause, cardiovascular and cancer mortality has not been explored before in community dwelling US adults. In a nationally representative cross-sectional survey of the US non-institutionalized population, all adult participants (≥20 years of age) using National Health and Nutrition Examination Survey data (1999-2010) combined with National Death Index for mortality status through December 2011. Cox proportional hazard models were built to estimate the hazard ratios for cardiovascular, cancer, and all-cause mortality for each unit increase in non-lactate SID. The models were adjusted for demographic and confounder variables. In the study population the mean (SD) age was 49.6 (18.4) years. Of the study population, 31,475 (91.5%) were alive and 2,893 (8.4%) died during the mean (SD) follow-up period of 5.5 (3.5) years. In univariate regression model using nlSID as continuous variable, we found 2% (unadjusted hazard ratio, HR=1.02; 95% CI, 1.004-1.05) increase in all-cause but not in cardiovascular and cancer mortality (HR=1.03; 95% CI, 0.99-1.08, HR=1.01; 95% CI, 0.97-1.06). After adjusting for potential confounders, we found 7% (adjusted HR=1.07; 95% CI, 1.04-1.10), 5% (HR=1.05; 95% CI, 1.00-1.11) and 7% (HR=1.07; 95% CI, 1.02-1.12) increase in all-cause, cardiovascular, and cancer mortality. A high nlSID is associated with an increase in cardiovascular, cancer and all-cause mortality and may be a prognostic indicator of mortality in general adult population. These findings may provide a point of reference for further studies.


Burnout Comparison between Clinical and Basic Sciences Faculty of a Medical School and Evaluation of Related Factors.
Objective: It has been shown that clinical practice may be a risk factor for job burnout. On the other hand, annual income may have a protective effect on job burnout. Clinical faculty in contrast to basic sciences faculty members have higher income but are involve in clinical practice. Comparison between these two groups can clarify which factors have greater influence on burnout. As a second aim for this study, reliability and validity of the Persian version of Maslach burnout inventory general survey (MBI-GS) were evaluated as well. Method : This cross-sectional study was conducted at Shiraz Medical School in Iran and a total of 241 faculty members were randomly selected and burnout was measured by the Persian version of the Maslach burnout inventory general survey (MBI-GS). Results: Comparison of burnout between the two groups indicated that clinical faculty showed significantly higher scores in the exhaustion dimension compared to the basic sciences faculty (p value = 0.017) but no significant differences were found between the two groups in other dimensions. Job satisfaction and income satisfaction were negatively correlated with exhaustion and cynicism dimensions, and job satisfaction was positively associated with professional efficacy (p value > 0.05). Internal consistency of the questionnaire was acceptable (α=0.77). Scaling success rate for discrimination and convergent validity were 100% except for convergent validity in the cynicism subscale. Correlation of all questions with their dimensions was equal to or more than 0.4 with the exception of item 13 in the cynicism subscale. Conclusion: Clinical faculty had higher burnout than basic sciences faculty especially in the exhaustion dimension. It has also been shown that income and job satisfaction are the most important factors which can predict professional burnout in medical faculty members. It is important for administrative and organizational decision makers to improve job engagement and decrease job abandonment. This study largely confirmed the 3-dimensional structure of the Persian version of MBI-GS.


[Application of nanopore sequencing in environmental microbiology research].
The development of high-throughput sequencing techniques enabled a deeper and more comprehensive understanding of environmental microbiology. Specifically, the third-generation sequencing techniques represented by nanopore sequencing have greatly promoted the development of environmental microbiology research due to its advantages such as long sequencing reads, fast sequencing speed, real-time monitoring of sequencing data, and convenient machine carrying, as well as no GC bias and no PCR amplification requirement. This review briefly summarized the technical principle and characteristics of nanopore sequencing, followed by discussing the application of nanopore sequencing techniques in the amplicon sequencing, metagenome sequencing and whole genome sequencing of environmental microorganisms. The advantages and challenges of nanopore sequencing in the application of environmental microbiology research were also analyzed.


Aroma retention in sol-gel-made silica particles.
The retention performance of aroma molecules from different chemical classes (e.g., alcohols, esters, aldehydes, and terpenes) by silica particles made by hydrolysis of tetraethyl orthosilicate is investigated. Since particle morphology, porosity, and pore size distribution can be controlled by the sol-gel preparation method, the influence of the nanoconfinement in the microporous matrix on aroma retention is studied as well as the effect of the initial aroma load of the particles. As the porosity is decreased, aroma molecules are entrapped more efficiently in the silica particles. The retention performance decreased from alcohols > aldehydes >/= esters > terpenes as with polar organic matrices. Open sol-gel-made silica particles show an increased retention with increasing aroma load, while denser silica matrices show a maximum retention with increasing load.


Addressing the Potential Need for Coronary Artery Bypass Grafting After Free Tissue Transfer for Breast Reconstruction: An Algorithmic Approach.
The number one cause of death in American women is heart disease. Studies have clearly shown the superiority of internal mammary artery (IMA) grafts for coronary revascularization over other conduits or intracoronary techniques. Our goal was to design an algorithm for recipient vessel selection in patients undergoing free tissue transfer breast reconstruction.A review of the literature was performed to identify potential evidence to contribute to a best-practice guideline. The lack of high-level evidence led us to create a guideline based on a workgroup consensus, expert opinion, cadaveric studies, and case reports.As we operate on older patient populations, the need for IMA use for coronary artery bypass grafting (CABG) after autologous breast reconstruction may arise more frequently. We discuss the current literature regarding recipient vessel choices and level of recipient vessel harvest in free flap breast reconstruction to help continually evolve the practices of our specialty to the potential future needs of our patients. We also present a best-practice decision algorithm for vessel selection and harvest, as well as a sample case of CABG using the left IMA 35 days after previous autologous breast reconstruction using the left IMA.As the number of patients we operate on who may later require their IMA for CABG increases, so too must our understanding of the implications of our selection of recipient vessels for free autologous breast reconstruction.


Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features.
Necroptosis, necrosis and secondary necrosis following apoptosis represent different modes of cell death that eventually result in similar cellular morphology including rounding of the cell, cytoplasmic swelling, rupture of the plasma membrane and spilling of the intracellular content. Subcellular events during tumor necrosis factor (TNF)-induced necroptosis, H(2)O(2)-induced necrosis and anti-Fas-induced secondary necrosis were studied using high-resolution time-lapse microscopy. The cellular disintegration phase of the three types of necrosis is characterized by an identical sequence of subcellular events, including oxidative burst, mitochondrial membrane hyperpolarization, lysosomal membrane permeabilization and plasma membrane permeabilization, although with different kinetics. H(2)O(2)-induced necrosis starts immediately by lysosomal permeabilization. In contrast, during TNF-mediated necroptosis and anti-Fas-induced secondary necrosis, this is a late event preceded by a defined signaling phase. TNF-induced necroptosis depends on receptor-interacting protein-1 kinase, mitochondrial complex I and cytosolic phospholipase A(2) activities, whereas H(2)O(2)-induced necrosis requires iron-dependent Fenton reactions.


Clustered DNA damages induced in isolated DNA and in human cells by low doses of ionizing radiation.
Clustered DNA damages-two or more closely spaced damages (strand breaks, abasic sites, or oxidized bases) on opposing strands-are suspects as critical lesions producing lethal and mutagenic effects of ionizing radiation. However, as a result of the lack of methods for measuring damage clusters induced by ionizing radiation in genomic DNA, neither the frequencies of their production by physiological doses of radiation, nor their repairability, nor their biological effects are known. On the basis of methods that we developed for quantitating damages in large DNAs, we have devised and validated a way of measuring ionizing radiation-induced clustered lesions in genomic DNA, including DNA from human cells. DNA is treated with an endonuclease that induces a single-strand cleavage at an oxidized base or abasic site. If there are two closely spaced damages on opposing strands, such cleavage will reduce the size of the DNA on a nondenaturing gel. We show that ionizing radiation does induce clustered DNA damages containing abasic sites, oxidized purines, or oxidized pyrimidines. Further, the frequency of each of these cluster classes is comparable to that of frank double-strand breaks; among all complex damages induced by ionizing radiation, double-strand breaks are only about 20%, with other clustered damage constituting some 80%. We also show that even low doses (0.1-1 Gy) of high linear energy transfer ionizing radiation induce clustered damages in human cells.


Cu(II)-mediated C-H amidation and amination of arenes: exceptional compatibility with heterocycles.
A Cu(OAc)2-mediated C-H amidation and amination of arenes and heteroarenes has been developed using a readily removable directing group. A wide range of sulfonamides, amides, and anilines function as amine donors in this reaction. Heterocycles present in both reactants are tolerated, making this a broadly applicable method for the synthesis of a family of inhibitors including 2-benzamidobenzoic acids and N-phenylaminobenzoates.


Photonastic Control of Leaflet Orientation in Melilotus indicus (Fabaceae).
Leaflet orientation in Melilotus indicus (L.) All. Is under photonastic control during the day and nyctinastic control during the night, but also exhibits a diaphototropic (solar-tracking) response. Detached leaves with the two lateral leaflets excised were used to study the solar-tracking capability of the terminal leaflet. Perception of the photonastic excitation is located in the pulvinule. The lower (abaxial) and upper (adaxial) surfaces perceive photonastic excitation, which results in concomitant contraction of the side exposed to light and/or expansion of the opposite side. Steady state laminar elevation is determined by the fluence rates of the light incident simultaneously on the opposite sides. Light sensitivity of the lower side exceeds that of the upper. Response to photonastic excitation of either side is affected by angle of incidence of the light, but angular dependence is restricted to a limited range of angle of incidence, which differs for the two sides. This may be accounted for by the different topography of the two pulvinar surfaces and the localization in them of the light-sensitive tissues.


Epitope mapping of anti-drug antibodies to a clinical candidate bispecific antibody.
Anti-drug antibodies (ADA) can limit the efficacy and safety of therapeutic antibodies. However, determining the exact nature of ADA interactions with the target drug via epitope mapping is challenging due to the polyclonal nature of the IgG response. Here, we demonstrate successful proof-of-concept for the application of hydroxyl radical footprinting (HRF)-mass spectrometry for epitope mapping of ADAs obtained from goats that were administered a knob-into-hole bispecific antibody (BsAb1). Subsequently, we performed epitope mapping of ADAs obtained from cynomolgus (cyno) monkeys that were administered BsAb1 as we described in a recently published paper. Herein, we provide the first data to demonstrate the feasibility of using HRF for ADA epitope mapping, and show that both goat and cyno-derived ADAs specifically target the complementary-determining regions in both arms of BsAb1, suggesting that the ADA epitopes on BsAb1 may be species-independent.


Acute chest pain-a stepwise approach, the challenge of the correct clinical diagnosis.
To assess the safety and the accuracy of a 4 h stepwise diagnostic approach relying on clinical judgement in unselected patients with acute chest pain. Prospective cohort study. Emergency department (ED) of a tertiary care university hospital. 1288 unselected patients presenting with acute chest pain. After history and physical examination, clinical judgement (step I), governed the need for further patient evaluation: baseline 12 lead electrocardiogramm (ECG) and laboratory examinations (step II), serial 12 lead ECG and laboratory examinations after 4 h (step III), and 4 h troponin T measurement (step IV) to exclude or to confirm a coronary origin of chest pain. Patients were followed clinically for 6 months for future occurrence of cardiac events (myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA), CABG, cardiac death), any death and for accuracy of the ED diagnosis in non-coronary chest pain patients. Chest pain was diagnosed to be coronary in origin in 381 and non-coronary in 907 patients, respectively. Cardiac events occurred during follow up in 240 (19%) of 1288 patients, in 233 of 381 (61%) with presumed coronary and seven of 907 (1%) with presumed non-coronary chest pain. Sensitivity, specificity, positive predictive value and negative predictive value for correct detection of coronary chest pain were 97, 86, 61 and 99%, respectively. In non-coronary chest pain patients the agreement between the ED diagnosis and the final diagnosis was good (kappa=0.71, 95% confidence interval (CI) 0.67-0.75). The 4 h stepwise approach guided by clinical judgement was safe for ruling out impending cardiac events in unselected patients with acute chest pain. However, more extensive evaluation is necessary for accurate rule-in of coronary chest pain.


Subclinical hypothyroidism in atopic South Italian children.
To verify if subclinical hypothyroidism (SCH) could be associated to atopy in children. Seven hundred and thirty-two Caucasian children from South Italy presenting symptoms of allergic disease were enrolled and submitted to atopy, obesity, chronic low grade inflammation, and SCH work up. Four hundred and forty-five out of 705 (63.12%) children affected by allergic disease were diagnosed as atopic and 260 (36.88%) as not atopic. The SCH prevalence was 6.3%. Significant higher prevalence of SCH among atopic children with average (group 2) and high (group 3) low grade chronic inflammation compared to atopic children with mild (group 1) low grade chronic inflammation was present. Moreover, group 1 and group 2 presented an OR to show SCH of 2.57 (95%CI: 1.55-6.26) and 2.96 (95%CI: 1.01-8.65), respectively. Both in atopic and not atopic children we found C3 serum levels significantly higher in group 3 respect to group 2 and group 1. Noteworthy, among atopic patients, also total immunoglobulin E (IgE) serum levels, were significantly higher in group 3 compared to group 2 and group 1 children. In atopic children, C3 and total IgE serum values increased in parallel with the increase of C-reactive protein values, while in not atopic children this phenomenon was not evident. The possibility exists that an increasing atopic inflammation contributes to SCH occurrence. So far this is the first report in literature showing an association between SCH and atopy but further studies are needed to confirm our data.


Synthesis and antihypertensive activities of new 1,4-dihydropyridine containing nitroimidazolyl substituent with a nitrooxy group at the 3-ester position.
New analogues of nifedipine, in which the ortho nitrophenyl group of position 4 is replaced by 1-methyl-4-nitro-5-imidazolyl or 1-methyl-5-imidazolyl with a nitrooxy group at the 3-ester position were synthesized, and the antihypertensive activity of the compounds was examined by the tail-cuff method and compared with TNG and nifedipine. Compounds 11g, 11i-11m, 11o, 11r, and 11v showed activity similar to nifedipine and TNG.


Targeted Photodynamic Diagnosis and Therapy for Esophageal Cancer: Potential Role of Functionalized Nanomedicine.
Esophageal cancer is often diagnosed at the late stage when cancer has already spread and is characterized by a poor prognosis. Therefore, early diagnosis is vital for a better and efficient treatment outcome. Upper endoscopy with biopsy is the standard diagnostic tool for esophageal cancer but is challenging to diagnose at its premalignant stage, while conventional treatments such as surgery, chemotherapy, and irradiation therapy, are challenging to eliminate the tumor. Photodynamic diagnosis (PDD) and therapy (PDT) modalities that employ photosensitizers (PSs) are emerging diagnostic and therapeutic strategies for esophageal cancer. However, some flaws associated with the classic PSs have limited their clinical applications. Functionalized nanomedicine has emerged as a potential drug delivery system to enhance PS drug biodistribution and cellular internalization. The conjugation of PSs with functionalized nanomedicine enables increased localization within esophageal cancer cells due to improved solubility and stability in blood circulation. This review highlights PS drugs used for PDD and PDT for esophageal cancer. In addition, it focuses on the various functionalized nanomedicine explored for esophageal cancer and their role in targeted PDD and PDT for diagnosis and treatment.


Adeno-associated viral vector 2.9 thymosin ß4 application attenuates rejection after heart transplantation: results of a preclinical study in the pig.
Graft survival is the most important factor for morbidity and mortality in cardiac transplantation. Improved immunosuppression significantly reduced early graft rejection. However, acute rejection may predispose to chronic rejection. Targeting both phases of the recipient's immune-reactivity by means of long-acting recombinant adeno-associated viral vectors (AAVs) encoding anti-inflammatory and cardioprotective factors appears to be a promising therapeutic approach. We investigate thymosin ß4 (Tß4) possessing anti-inflammatory and prosurvival abilities, as a means for pretransplant gene therapy. Heterotopic, abdominal transplantation of cardiac allografts into landrace or into Munich mini pigs (n=5 per group) was performed. Transplants were transduced with AAV2.9 before transplantation by means of in situ perfusion of the donor organ. Vascuar endothelial growth factor and AAV2.9.Tß4 or AAV2.9.LacZ were added to the autologous blood used for perfusing the grafts for a period of 45 min. Immunosuppression was applied for 10 days after the operation. Transgene expression, capillary density, graft function, survival, and rejection were assessed. The AAV2.9 transduction induced robust overexpression of the transgene. In addition, Tß4 ameliorated inflammation, necrosis, vascular reaction (acute rejection) and in parallel improved capillary density. In addition, graft survival was significantly prolonged (10±3 days AAV2.9.LacZ vs. 31±4 days AAV2.9.Tß4). In the mini pig model, regional myocardial function of the grafts was improved by Tß4 transduction compared to LacZ (9.1%±0.9% subendocardial segment shortening in AAV2.9.LacZ vs. 15.8%±2.3% in AAV2.9.Tß4). In situ AAV2.9-mediated gene transfer of thymosin β4 attenuated graft rejection in a heterotopic heart transplantation model. Perioperative cardioprotection by means of gene therapy might improve graft survival in cardiac allotransplantation.


Profiling genes differentially expressed in NGX6 overexpressed nasopharyngeal carcinoma cells by cDNA array.
To investigate the role of the NGX6 gene in carcinoma proliferation and profile the downstream genes regulated by NGX6 in a nasopharyngeal carcinoma (NPC) cell line. We established a NPC cell line with NGX6 overexpression by gene transfection. Subsequently, a high-density cDNA array was used to identify differentially expressed genes in NGX6-overxepressed cells. Four differentially expressed genes or EST(expressed sequence tags) were examined using Northern blot. Furthermore, flow cytometry was employed to analyze the percentages of cells in the G(0)-G(1), S, and G(2)-M phase of the cell cycle in a NGX6 overexpression cell line. Fifty-five genes and ESTs were differentially expressed after NGX6 transfection in a cDNA array assay. Several genes related to cell cycle and transcription regulation were identified using this technique. Flow cytometry analysis showed NGX6 overexpression can increase the length of the G(1) phase of the cell cycle in NPC cells. We demonstrated the existence of a panel of genes that can be regulated by NGX6. Overexpression of NGX6 can influence the distribution of the cell cycle in NPC cells. Further studies are necessary to elucidate the exact function of these genes and their relationship to NGX6 expression.


Diurnal variation in airborne pollen concentrations of the selected taxa in Zagreb, Croatia.
The number of individuals allergic to plant pollen has recently been on a constant increase. The knowledge of diurnal distribution and abundance of allergenic pollen types, their patterns and response to source position and weather is useful to correlate hay fever symptoms with the presence of allergenic pollen in the atmosphere. The aim of this study was to determine diurnal distribution of total airborne pollen, pollen of particular allergenic taxa, possible variation in diurnal pollen distribution at measuring sites placed at different heights, and effect of some meteorological parameters on airborne pollen concentrations. A 7-day Hirst-type volumetric pollen trap was used for pollen sampling. Qualitative and quantitative pollen analysis was performed under a light microscope (magnification x400). Total pollen of all plant taxa (Ambrosia sp., Betula sp., Cupressaceae, Urticaceae, Poaceae, Quercus sp., Fraxinus sp., Alnus sp., Corylus sp., Populus sp., Pinus sp., Picea sp.) observed showed a regular diurnal distribution at both sampling sites in both study years, with a rise in the pollen concentration recorded after 4.00 a.m. and 6.00 a.m., respectively. The peak pollen concentration occurred between 12.00 a.m. and 4.00 p.m., and the lowest diurnal pollen concentrations were recorded overnight. About 50% of the 24-h pollen concentration were released to the atmosphere between 10.00 a.m. and 4.00 p.m. The timing and size of diurnal peaks were closely related to high temperature, low humidity and south-west maximum wind direction.


Interactions of low temperature, water stress, and short days in the induction of stem frost hardiness in red osier dogwood.
The induction of stem frost hardiness by low temperature, water stress, short days, and their combinations in 2- and 4-month-old growing dogwoods (Cornus stolonifera) were investigated. When plants were subjected to more than one factor, the increased hardiness was the sum of the effects of the individual factors involved. No interactions among these factors on hardiness were observed during a 3-week treatment. Results indicate that low temperature, water stress, and short days initially trigger independent frost-hardening mechanisms. Plant ages significantly influenced the change in low temperature-induced frost hardiness, but not the water stress or short day-induced frost hardiness.


CRP Is Transported by Monocytes and Monocyte-Derived Exosomes in the Blood of Patients with Coronary Artery Disease.
The objective of this work was to study the ability of blood cells and their microparticles to transport monomeric and pentameric forms of C-reactive protein (mCRP and pCRP) in the blood of patients with coronary artery disease (CAD). Blood was obtained from 14 patients with CAD 46 ± 13 years old and 8 healthy volunteers 49 ± 13.6 years old. Blood cells and microparticles with mCRP and pCRP on their surface were detected by flow cytometry. Messenger RNA (mRNA) of CRP was extracted from peripheral blood monocytes stimulated with lipopolysaccharide (LPS) and granulocyte-macrophage colony-stimulating factor (GM-CSF). mRNA of CRP in monocytes was detected with PCR. Monocytes were predominantly pCRP-positive (92.9 ± 6.8%). mCRP was present on 22.0 ± 9.6% of monocyte-derived exosomes. mCRP-positive leukocyte-derived microparticle counts were significantly higher (8764 ± 2876/µL) in the blood of patients with CAD than in healthy volunteers (1472 ± 307/µL). LPS and GM-CSF stimulated monocytes expressed CRP mRNA transcripts levels (0.79 ± 0.73-fold), slightly lower relative to unstimulated hepatocytes of the HepG2 cell line (1.0 ± 0.6-fold), but still detectable. The ability of monocytes to transport pCRP in blood flow, and monocyte-derived exosomes to transmit mCRP, may contribute to the maintenance of chronic inflammation in CAD.


The Glyoxysomal Protease LON2 Is Involved in Fruiting-Body Development, Ascosporogenesis and Stress Resistance in Sordaria macrospora.
Microbodies, including peroxisomes, glyoxysomes and Woronin bodies, are ubiquitous dynamic organelles that play important roles in fungal development. The ATP-dependent chaperone and protease family Lon that maintain protein quality control within the organelle significantly regulate the functionality of microbodies. The filamentous ascomycete Sordaria macrospora is a model organism for studying fruiting-body development. The genome of S. macrospora encodes one Lon protease with the C-terminal peroxisomal targeting signal (PTS1) serine-arginine-leucine (SRL) for import into microbodies. Here, we investigated the function of the protease SmLON2 in sexual development and during growth under stress conditions. Localization studies revealed a predominant localization of SmLON2 in glyoxysomes. This localization depends on PTS1, since a variant without the C-terminal SRL motif was localized in the cytoplasm. A ΔSmlon2 mutant displayed a massive production of aerial hyphae, and produced a reduced number of fruiting bodies and ascospores. In addition, the growth of the ΔSmlon2 mutant was completely blocked under mild oxidative stress conditions. Most of the defects could be complemented with both variants of SmLON2, with and without PTS1, suggesting a dual function of SmLON2, not only in microbody, but also in cytosolic protein quality control.


Exosite interactions impact matrix metalloproteinase collagen specificities.
Members of the matrix metalloproteinase (MMP) family selectively cleave collagens in vivo. However, the substrate structural determinants that facilitate interaction with specific MMPs are not well defined. We hypothesized that type I-III collagen sequences located N- or C-terminal to the physiological cleavage site mediate substrate selectivity among MMP-1, MMP-2, MMP-8, MMP-13, and MMP-14/membrane-type 1 (MT1)-MMP. The enzyme kinetics for hydrolysis of three fluorogenic triple-helical peptides (fTHPs) was evaluated herein. The first fTHP contained consensus residues 769-783 from type I-III collagens, the second inserted α1(II) collagen residues 763-768 N-terminal to the consensus sequence, and the third inserted α1(II) collagen residues 784-792 C-terminal to the consensus sequence. Our analyses showed that insertion of the C-terminal residues significantly increased k(cat)/K(m) and k(cat) for MMP-1. MMP-13 showed the opposite behavior with a decreased k(cat)/K(m) and k(cat) and a greatly improved K(m) in response to the C-terminal residues. Insertion of the N-terminal residues enhanced k(cat)/K(m) and k(cat) for MMP-8 and MT1-MMP. For MMP-2, the C-terminal residues enhanced K(m) and dramatically decreased k(cat), resulting in a decrease in the overall activity. These changes in activities and kinetic parameters represented the collagen preferences of MMP-8, MMP-13, and MT1-MMP well. Thus, interactions with secondary binding sites (exosites) helped direct the specificity of these enzymes. However, MMP-1 collagen preferences were not recapitulated by the fTHP studies. The preference of MMP-1 for type III collagen appears to be primarily based on the flexibility of the hydrolysis site of type III collagen compared with types I and II. Further characterization of exosite determinants that govern interactions of MMPs with collagenous substrates should aid the development of pharmacotherapeutics that target individual MMPs.


In silico approach for enhancing innate lipid content of Yarrowia lipolytica, by blocking the acyl-CoA oxidase-1 enzyme, using various analogous compounds of lipids.
Yarrowia lipolytica is used as a model in this study to screen the potential candidates for inflating the innate lipid content of the cell. This study focuses on reducing the lipid degradation that occurs by the β-oxidation process and discursively increasing the innate lipid content. Acyl-CoA oxidase-1, the primary and initial enzyme involved in the lipid degradation pathway, was selected as a target and blocked using various lipid analogous compounds. The blocking study was carried out using molecular docking and dynamic studies using computation tools. The largest active site pocket located around the Phe-394 amino acid of the target protein is taken as a site for docking. The molecular docking was performed for the selected compounds (citric acid, Finsolv, lactic acid, oxalic acid, Tween-80 and Triton X-100) and the docking results were compared with the outcome of the standard molecule (octadecatrienoic acid). Citric acid, Finsolv, Tween-80 and Triton X-100 were found to be the potential candidates for blocking the target molecule in the static condition using docking studies, revealing a minimum binding energy requirement than the standard molecule. They were further taken for a dynamics study using GROMACS software. The RMSD, RMSF, number of hydrogen bond interactions and radius of gyration of the complex molecules were studied in a dynamic approach for 100 ns. Citric acid has been found to be the potential hit compound to block acyl-CoA oxidase-1 enzyme with its maximum hydrogen interaction and minimum fluctuations. It also revealed out the minimum total energy requirement for the complex formation.


IGF-I resistance in virus-transformed B-lymphocytes from African Efe Pygmies.
To investigate IGF-I resistance in African Efe Pygmies, we examined clonal responsiveness to IGF-I in Epstein-Barr virus-transformed B-lymphocytes from three Efe Pygmies and three American control subjects. The Efe B-lymphoblasts did not increase clonal responsiveness when incubated with IGF-I (as high as 250 micrograms/liter) in contrast to the control B-lymphoblasts which showed a bimodal dose-response with a maximal stimulation of 50% above baseline. The proliferative response of Efe B-lymphoblasts was similar to that of control B-lymphoblasts when incubated with another growth factor, phorbol 12-myristate 13-acetate, which does not activate the IGF-I receptor. These findings indicate that Efe Pygmy B-lymphoblasts are resistant to IGF-I as measured by in vitro clonal proliferation assays. Coupled with our previous report of IGF-I unresponsiveness in Efe Pygmy HTLV-II-transformed T-lymphocytes, these data suggest that IGF-I resistance is generalized and may play a central role in the etiology of short stature in this population.


[Step-test on surveillance of students' physical fitness and health].
To analyze the role of step-test on large sample surveillance in students' physical fitness and health. Totally, 36 237 students aged 12-, 14- and 17-year-old from fifteen Chinese provinces taking part in the 2004th National Surveillance on Students' Physical Fitness and Health were enrolled in this study. All of them passed through the step-test, of which the indices were calculated in combining with the performance time and pulse rates in resuming period. The means of step-test index were analyzed among various youth groups, and compared with the obesity, overweight and the normal-weight subjects. As compared with the general level of physical growth, the means of step-test index were found higher in rural groups than in urban ones, and higher in southern groups than in northern ones. The highest means of index was found in the rural groups in having the lowest socioeconomic status, and also the lowest means found in metropolis groups having the highest socioeconomic status. These gaps were due to the change of life style, absence of physical exercise and relatively to the high body weight of the high socioeconomic-level groups. Among the obesity, overweight and normal-weight youths, the means of step-test index was shown in a gradient decrease tendency, and those significant gaps might be found between the obesity and the overweight, and the overweight and the normal-weight groups, showing that there should be harmful influences of overweight and obesity on the youth's cardiovascular function. As a safe and easily-taken measure for cardiovascular function, the step-test should be useful in regularly measuring the national students' physical fitness and health status.


Phenotypic and Molecular Cytogenetic Analysis of a Case of Monosomy 1p36 Syndrome due to Unbalanced Translocation.
Monosomy 1p36 syndrome is one of the most common submicroscopic deletion syndromes, which is characterized by the presence of delayed developmental milestones, intellectual disability, and clinically recognizable dysmorphic craniofacial features. The syndrome comprises 4 cytogenetic groups including pure terminal deletions, interstitial deletions, complex rearrangements, and derivative chromosomes 1 due to unbalanced translocations, where unbalanced translocations represent the least percentage of all cases of monosomy 1p36 (7%). Most patients with monosomy 1p36 due to an unbalanced translocation can be cytogenetically diagnosed using conventional techniques. However, chromosomal microarray analysis is mandatory in these cases to detect copy number variance and size of the deletion and allows for setting a phenotype-genotype correlation. Here, we studied a 1.5-year-old female patient who showed intellectual disability, delayed milestones, hypotonia, seizures, and characteristic dysmorphic features including brachycephaly, straight eyebrows, deep-set eyes, downslanting palpebral fissures, midface hypoplasia, depressed nasal bridge, long philtrum, and pointed chin. Conventional cytogenetic analysis (CCA), microarray study, and fluorescence in situ hybridization (FISH) analysis were performed. CCA showed a translocation involving chromosomes 1 and 21, 45,XX,der(1)t(1;21)(p36.32;q21.1)dn. Microarray analysis revealed copy number losses at both 1p36 and proximal 21q. FISH confirmed the presence of the 1p36 deletion, but was not performed for 21q. We have concluded that phenotype-genotype correlation for monosomy 1p36 syndrome can be performed for the fundamental clinical manifestations; however, the final aspect of the syndrome depends on composite factors. Monosomy 1p36 due to unbalanced translocation may present either classically or with additional altered features of various severity based on the copy number variations involving different chromosomes.


Effectiveness of a rehabilitative program that integrates hospital and community services for patients with schizophrenia in one community in Shanghai.
One possible reason for the less than satisfactory long-term outcomes for schizophrenia is the lack of coordination between inpatient and community-based services. Assess the effectiveness of a rehabilitation model for schizophrenia that integrates hospital and community services. Ninety patients with schizophrenia participating in an integrated rehabilitation program at 10 community centers in Changning, Shanghai (intervention group) and 52 community-based patients with schizophrenia randomly selected from all patients in Changning participating in routine outpatient care (control group) were assessed at enrollment using the Positive and Negative Syndrome Scale (PANSS) and the Morningside Rehabilitation Status Scale (MRSS) and then re-assessed 1 year later by clinicians who were blind to the group assignment of the patients. The patients' registered guardians (the vast majority were co-resident family members) were assessed at the same times using the Family Burden Scale (FBS), the Self-rating Depression Scale (SDS), the Self-rating Anxiety Scale (SAS) and the Social Support Rating Scale (SSRS). At enrollment the clinical status of patients in the two groups (assessed with PANSS) was similar but the social functioning measures assessed by MRSS were significantly worse in the intervention group than in the control group. After one year the improvement of both clinical symptoms and social functioning measures were significantly greater in the intervention group than in the control group. In the year of follow-up, 3 individuals (3.3%) in the intervention group and 6 individuals (11.5%) in the control group were re-hospitalized (Fisher Exact Test, p=0.074). The feelings of burden, depression, anxiety and reported social support among guardians of patients in the intervention group were not significantly different from those for guardians of patients in the control group either at the time of enrollment or after the 1-year intervention. However, guardians in the intervention group showed a significant decrease in depressive and anxiety symptoms over the one-year follow-up. Rehabilitative approaches that integrate hospital and community services can improve clinical and social outcomes for patients with schizophrenia. Further development of these programs is needed to increase the proportion of patients who achieve regular employment (i.e., 'community re-integration') and to provide family members with better psychosocial support.


Characterization of a novel human SMC heterodimer homologous to the Schizosaccharomyces pombe Rad18/Spr18 complex.
The structural maintenance of chromosomes (SMC) protein encoded by the fission yeast rad18 gene is involved in several DNA repair processes and has an essential function in DNA replication and mitotic control. It has a heterodimeric partner SMC protein, Spr18, with which it forms the core of a multiprotein complex. We have now isolated the human orthologues of rad18 and spr18 and designated them hSMC6 and hSMC5. Both proteins are about 1100 amino acids in length and are 27-28% identical to their fission yeast orthologues, with much greater identity within their N- and C-terminal globular domains. The hSMC6 and hSMC5 proteins interact to form a tight complex analogous to the yeast Rad18/Spr18 heterodimer. In proliferating human cells the proteins are bound to both chromatin and the nucleoskeleton. In addition, we have detected a phosphorylated form of hSMC6 that localizes to interchromatin granule clusters. Both the total level of hSMC6 and its phosphorylated form remain constant through the cell cycle. Both hSMC5 and hSMC6 proteins are expressed at extremely high levels in the testis and associate with the sex chromosomes in the late stages of meiotic prophase, suggesting a possible role for these proteins in meiosis.


Insight into emission-tuning and luminescence thermal quenching investigations in NaLa1-xGdxCa4W2O12:Mn4+ phosphors via the ionic couple substitution of Na+ + Ln3+ (Ln = La, Gd) for 2Ca2+ in Ca6W2O12:Mn4+ for plant-cultivation LED applications.
In this work, a series of novel NaLa1-xGdxCa4W2O12:Mn4+ (NL1-xGxCWO:Mn4+, x = 0-1) phosphors were synthesized using a high-temperature solid-state reaction approach. Unexpected intense red-far-red emissions were clearly observed after the ionic couple substitution of 2Ca2+ by Na+ + Ln3+ (Ln = La, Gd) in negligible-luminescence Ca6W2O12:Mn4+ upon ultraviolet (UV) excitation. Moreover, a maximal emission-tuning of Δλ = 28 nm (Δν = 582 cm-1) can be found by changing x from 0 to 1, which is ascribed to the different crystal field and covalence among them. In addition, the luminescence thermal quenching behaviors and thermal quenching mechanisms were investigated in detail in representative NLCWO:0.01Mn4+ and NGCWO:0.01Mn4+ phosphors. The results were used to initiate an ionic couple substitution strategy to enrich novel oxide hosts for Mn4+ luminescence and select an appropriate host with better thermal stability for plant-cultivation LED applications.


Molecular targeted therapies for rhabdomyosarcoma: focus on hedgehog and apoptosis signaling.
Dysfunction of cell death and proliferation pathways can contribute to rhabdomyosarcomagenesis, tumor progression and treatment resistance. Therefore, the identification of key signaling hubs and molecules that govern the decision between life and death of a cancer cell is expected to open new perspectives for drug discovery. For example, programmed cell death pathways can be engaged in rhabdomyosarcoma (RMS) cells by recombinant soluble proteins, monoclonal antibodies or small-molecule inhibitors. In addition, the hedgehog (Hh) cascade is often aberrantly activated in RMS and represents a promising target for therapeutic intervention. The development of molecular targeted cancer therapeutics will likely lead to more effective treatment options for patients with RMS.


Standardization of LC-MS for therapeutic drug monitoring of tacrolimus.
LC-MS is increasingly used for therapeutic drug monitoring of tacrolimus. A recent summary from an international proficiency-testing scheme demonstrated that the mass spectrometry respondents were the largest method group. However, these methods lack standardization, which may explain the relatively poor interlaboratory agreement for such methods. This study aimed to provide one path toward the standardization of tacrolimus quantification by use of LC-MS. A 40-member whole blood tacrolimus proficiency panel was circulated to 7 laboratories, 4 in the US and 3 in Europe, offering routine LC-MS-based quantification of tacrolimus. All laboratories used a common LC-MS platform and followed the manufacturer's instructions that accompanied an LC-MS reagent kit intended for tacrolimus quantification in whole blood samples. Four patient pools were prepared that had sufficient volume to allow comparison with a tacrolimus reference measurement procedure. For the 40-member panel, the standardized MassTrak LC-MS assay demonstrated excellent agreement with a validated LC-MS method used by Analytical Services International (y = 1.02x - 0.02; r = 0.99). The CVs for the pooled patient samples ranged from 2.0% to 5.4%. The mean difference from the reference measurement procedure ranged from 0.4% to 4.4%. Tacrolimus assay standardization, which must include all facets of the analysis, is necessary to compare patient results between laboratories and to interpret consensus guidelines. LC-MS can provide accurate and precise measurement of tacrolimus between laboratories.


[Infective endocarditis associated with pregnancy].
To report the intra-hospitalar and late follow-up of patients with infective endocarditis (IE) acquired in the pregnancy or puerperium. Eleven patients, between 1984-1992 according to the beginning of the IE episode (fever and other signals) were studied. Patients were divided in two groups: IE of pregnancy (7 cases), and puerperal IE (4 cases). In the pregnancy IE group, mitral valve was affected in 6 (85%), and aortic valve in 1 (15%). During the course of the treatment, two patients had to be operated on, respectively, in the 24th and 28th week of the pregnancy. The 1st one had a successfully mitral valve replacement by a biological prosthesis but 48 h later she aborted, and the 2nd presented neurological complication (intracerebral hemorrhage) in the immediate post-operative period of a successfully mitral valve replacement by biological prosthesis. She was undergone to a cesarean but the fetus remained alive for 24 h only. If we look at the newborns (fetus), only 4 of them survived. Out of 3 fetal deaths, 2 had close association with mother cardiac surgeries. In the pregnant period acquired IE, 3 (47%) mothers died. In the puerperium group, 2 mitral valves and 2 aortic valves had IE. Two of them had to be operated on due to an important aortic regurgitation and cardiac failure. There were no deaths in this group. During pregnancy, IE showed a high morbi-mortality for mother and concept. The mother's neurological complications played a major role in the poor outcome during the pregnancy period.


Interleukin-4 enhances the survival of severe combined immunodeficient mice engrafted with human B-cell precursor leukemia.
Human interleukin-4 (huIL-4) has been shown to inhibit the growth in vitro of cells from patients with acute lymphoblastic leukemia (ALL). With the aim of determining whether this cytokine might be useful in the treatment of patients with ALL, the effects of huIL-4 on human B-cell precursor ALL engrafted in severe combined immunodeficient (SCID) mice were examined. The inhibition of [3H] thymidine uptake of primary ALL cells by huIL-4 was maintained following engraftment and passage of leukemia in SCID mice. Five of seven xenograft leukemias showed significant inhibition in vitro by huIL-4 at concentrations as low as 0.5 ng/mL; furthermore, huIL-4 counteracted the proliferative effects of IL-7. When used to treat two human leukemias engrafted in SCID mice, huIL-4 200 microgram/kg/d, as a continuous 14-day subcutaneous infusion, suppressed the appearance of circulating lymphoblasts and extended survival of mice by 39% and 108%, respectively, the first demonstration of IL-4 activity against human leukemia in vivo. The mean steady-state huIL-4 level in mouse plasma during the infusion was 1.46 ng/mL (SEM +/- 0.14 ng/mL), which was similar to concentrations found to be effective in vitro. ALL cells obtained from mice relapsing after huIL-4 treatment continued to show inhibition by the cytokine in vitro. These data suggest that IL-4 may be useful in the treatment of patients with ALL.


Identification of Atrial Fibrillation-Associated Genes ERBB2 and MYPN Using Genome-Wide Association and Transcriptome Expression Profile Data on Left-Right Atrial Appendages.
More reliable methods are needed to uncover novel biomarkers associated with atrial fibrillation (AF). Our objective is to identify significant network modules and newly AF-associated genes by integrative genetic analysis approaches. The single nucleotide polymorphisms with nominal relevance significance from the AF-associated genome-wide association study (GWAS) data were converted into the GWAS discovery set using ProxyGeneLD, followed by merging with significant network modules constructed by weighted gene coexpression network analysis (WGCNA) from one expression profile data set, composed of left and right atrial appendages (LAA and RAA). In LAA, two distinct network modules were identified (blue: p = 0.0076; yellow: p = 0.023). Five AF-associated biomarkers were identified (ERBB2, HERC4, MYH7, MYPN, and PBXIP1), combined with the GWAS test set. In RAA, three distinct network modules were identified and only one AF-associated gene LOXL1 was determined. Using human LAA tissues by real-time quantitative polymerase chain reaction, the differentially expressive results of ERBB2, MYH7, and MYPN were observed (p < 0.05). This study first demonstrated the feasibility of fusing GWAS with expression profile data by ProxyGeneLD and WGCNA to explore AF-associated genes. In particular, two newly identified genes ERBB2 and MYPN via this approach contribute to further understanding the occurrence and development of AF, thereby offering preliminary data for subsequent studies.


Index of refraction measurement on sapphire at low temperatures and visible wavelengths.
The ordinary and extraordinary refractive index of two samples of sapphire, which differed in the way each was grown, was measured. The measurements were made over a wavelength range of 477-701 nm and a temperature range of 20-295 K. A three-term Sellmeier dispersion equation was fit to the data to permit refractive-index interpolation within several parts in 10(4). The data of index versus temperature were fit to a model and the results of dn/dT versus temperature are given along with certain physical constants that were extracted from the model.


Role of Pro-inflammatory Cytokines in Regulation of Skeletal Muscle Metabolism: A Systematic Review.
Metabolic pathways perturbations lead to skeletal muscular atrophy in the cachexia and sarcopenia due to increased catabolism. Pro-inflammatory cytokines induce the catabolic pathways that impair the muscle integrity and function. Hence, this review primarily concentrates on the effects of pro-inflammatory cytokines in regulation of skeletal muscle metabolism. This review will discuss the role of pro-inflammatory cytokines in skeletal muscles during muscle wasting conditions. Moreover, the coordination among the pro-inflammatory cytokines and their regulated molecular signaling pathways which increase the protein degradation will be discussed. During normal conditions, pro-inflammatory cytokines are required to balance anabolism and catabolism and to maintain normal myogenesis process. However, during muscle wasting their enhanced expression leads to marked destructive metabolism in the skeletal muscles. Proinflammatory cytokines primarily exert their effects by increasing the expression of calpains and E3 ligases as well as of Nf-κB, required for protein breakdown and local inflammation. Proinflammatory cytokines also locally suppress the IGF-1and insulin functions, hence increase the FoxO activation and decrease the Akt function, the central point of carbohydrates lipid and protein metabolism. Current advancements have revealed that the muscle mass loss during skeletal muscular atrophy is multifactorial. Despite great efforts, not even a single FDA approved drug is available in the market. It indicates the well-organized coordination among the pro-inflammatory cytokines that need to be further understood and explored.


SCN5A promoter haplotype affects the therapeutic range for serum flecainide concentration in Asian patients.
An increased slowing of cardiac conduction induced by sodium channel blockers is remarkably observed in carriers of an Asian-specific promoter haplotype [haplotype B (HapB)] of the cardiac sodium channel gene (SCN5A). We investigated the effect of HapB on the therapeutic range for serum flecainide concentration in Asian patients. We examined the serum concentration and antiarrhythmic efficacy of flecainide, together with the SCN5A promoter haplotype, in 146 patients with supraventricular tachyarrhythmias. Trough serum flecainide concentrations were determined by HPLC. The antiarrhythmic efficacy of flecainide was assessed for at least 2 months through examination of symptomatology, ECG, and Holter monitoring. The serum flecainide concentration did not differ between the wild-type HapA homozygotes and HapB carriers under treatment with the usual dose. A genetic difference in the antiarrhythmic efficacy of flecainide was observed between the HapA homozygotes and HapB carriers at serum flecainide concentrations less than 300 ng/ml (42.9 vs. 68.8%; P=0.022). PR prolongation and QRS widening were observed more commonly among the HapB carriers with serum flecainide concentrations of at least 300 ng/ml than in the HapA homozygotes (PR, 210 ± 25 vs. 195 ± 25 ms; P=0.036; and QRS, 112 ± 10 vs. 105 ± 9 ms; P=0.030). These findings suggest that the therapeutic range for serum flecainide concentration is lower in HapB carriers than in HapA homozygotes.


Boron and Coumaphos Residues in Hive Materials Following Treatments for the Control of Aethina tumida Murray.
In the search of alternatives for controlling Aethina tumida Murray, we recently proposed the BAA trap which uses boric acid and an attractant which mimics the process of fermentation caused by Kodamaea ohmeri in the hive. This yeast is excreted in the feces of A. tumida causing the fermentation of pollen and honey of infested hives and releasing compounds that function as aggregation pheromones to A. tumida. Since the boron is the toxic element in boric acid, the aim of this article is to assess the amount of boron residues in honey and beeswax from hives treated with the BAA trap. For this aim, the amount of bioaccumulated boron in products of untreated hives was first determined and then compared with the amount of boron of products from hives treated with the BAA trap in two distinct climatic and soil conditions. The study was conducted in the cities of Padilla, Tamaulipas, and Valladolid, Yucatan (Mexico) from August 2014 to March 2015. The quantity of boron in honey was significantly less in Yucatan than in Tamaulipas; this agrees with the boron deficiency among Luvisol and Leptosol soils found in Yucatan compared to the Vertisol soil found in Tamaulipas. In fact, the honey from Yucatan has lower boron levels than those reported in the literature. The BAA treatment was applied for four months, results show that the BAA trap does not have any residual effect in either honey or wax; i.e., there is no significant difference in boron content before and after treatment. On the other hand, the organophosphate pesticide coumaphos was found in 100% of wax samples and in 64% of honey samples collected from Yucatan. The concentration of coumaphos in honey ranges from 0.005 to 0.040 mg/kg, which are below Maximum Residue Limit (MRL) allowed in the European Union (0.1 mg/kg) but 7.14% of samples exceeded the MRL allowed in Canada (0.02 mg/kg).


Comparison of anatomically-defined versus physiologically-based regional localization: effects on PET-FDG quantitation.
The potential of anatomic imaging to improve the quantitative accuracy of functional brain imaging through refined regional definition is widely accepted. However, there are little data addressing the impact of approach to regional localization on quantitation of metabolic images in the absence of gross structural pathology. We compared MRI-based versus PET-based approaches to the analysis of PET 18F-fluorodeoxyglucose (FDG) images using a standard adjustable template based on simple geometric regions. For the MRI-based approach, templates and individual regions were adjusted to each individual's anatomy, whereas the PET-based definition involved only global proportional adjustment of the standard templates. Metabolic rates for glucose and volume-to-whole brain ratios were determined by two operators for 78 volumes of interest in five subjects. Pairwise correlations indicated high interoperator agreement for each approach and high intraoperator agreement for MRI-based versus PET-based metabolic values. The stability of the metabolic rates and ratios among operators and analysis approaches was supported by low coefficients of variation across measurements and small average differences in paired comparisons. Thus, within the current spatial resolution of PET imaging, quantitation of metabolic images is relatively robust to image analysis approach in the absence of gross structural abnormality. To take advantage of the greater quantitative accuracy promised by high-resolution anatomic and functional imaging, more refined delineation of anatomic images will be necessary.


Proliferation, DNA repair and apoptosis in androgenetic alopecia.
Androgenetic alopecia is a common hair disorder, resulting from interplay of genetic, endocrine and ageing factors. Meanwhile, it is unclear if an altered degree of proliferation or increased apoptosis could contribute to its pathogenesis. To evaluate the role of proliferation, DNA damage and apoptosis in the pathogenesis of androgenetic alopecia. Thirty biopsies were taken from the frontal (bald) area and occipital (hairy) area of 15 male patients with androgenetic alopecia, as well as five specimens from frontal area of five age-matched controls. These specimens were used for immunohistochemical staining of cell proliferation [proliferating cell nuclear antigen (PCNA)] and DNA repair markers (XRCC1, APE1, PARP-1) as well as apoptosis regulatory protein p53. The frontal bald area of patients showed significantly higher levels of X-ray Cross Complementing-1 (XRCC1; P<0.001) and p53 (P<0.001) expression when compared with occipital hairy area of patients and frontal area of controls (P=0.003 and 0.04, respectively). On the other hand, there were significantly lower expression of PCNA (P<0.001) and apurinic/apyridinic endonuclease 1 (APE1; P=0.001 and 0.02) when compared with the frontal area of controls and occipital area of patients, respectively. Meanwhile, APE1 showed significant inverse correlation with p53 overexpression (P=0.03). The frontal bald area of patients with androgenetic alopecia has lower proliferation rate that result in follicular miniaturization. There is increased DNA damage that would be beyond the capacity of cells to repair in advanced cases. An alternative pathway would take place in order to eliminate the damaged cells through apoptosis.


Host manipulation as a parasite transmission strategy when manipulation is exploited by non-host predators.
Trophically transmitted parasites often alter their intermediate host's phenotype, thereby predisposing hosts to increased predation. This is generally considered to be a parasite strategy evolved to enhance transmission to the next host. However, the adaptive value of host manipulation is not clear, as it may be associated with costs, such as increased susceptibility to predator species that are unsuitable next hosts for the parasites. Thus, it has been proposed that, to be adaptive, manipulation should be specific by predisposing hosts more strongly to predation by target hosts (next host in the life cycle) than to non-hosts. Here we formally evaluate this prediction, and show that manipulation does not have to be specific to be adaptive. However, when manipulation is nonspecific, it needs to effectively increase the overall predation risk of infected hosts if it is to increase the parasite transmission probability. Thus, when initial predation risk is low, even highly nonspecific manipulation strategies can be adaptive. However, when initial predation risk is high, manipulation needs to be more specific to increase parasite transmission success. Therefore, nonspecific host manipulation may evolve in nature, but the adaptive value of a certain manipulation strategy can vary among different parasite populations depending on the variation in initial predation risk.


Distinct short-term and long-term adaptation to reduce saccade size in monkey.
In monkeys, saccades that repeatedly overshoot their targets adapt to become smaller by the time the monkey has made 1,000-2,000 saccades. In life, adaptation must keep movements accurate for long periods of time. Previous work describes only saccade adaptation that occurs within a few hours. Here we describe long-term saccade adaptation elicited in three monkeys by 19 days of training. Each day a monkey made saccades to track 16 degrees leftward and rightward target movements. During saccades, the target stepped back toward its starting position 6.4 degrees (40%) in two monkeys or 8 degrees (50%) in the third. After each day's adaptation, we blindfolded the monkey with goggles and returned it to its cage overnight. We found that adapting saccades for 19 days elicited significantly larger, long-lasting reduction in saccade size than did adapting for only 1 day. Further, after 19 days of adaptation we could elicit additional, apparently normal, short-term reduction in saccade size by increasing the size of the intra-saccade target movement. In contrast, we could elicit only small additional size reduction after only 1 day of adaptation. A simple model using separate short- and long-term adaptation mechanisms can reproduce many of the features of saccade gain exhibited by monkeys during a 19-day adaptation. We conclude that there is a long-term saccade-adaptation mechanism that is distinct from the well-characterized short-term system and that this newly recognized system is responsible for long-term maintenance of saccade accuracy.


Phytoremediation of heavy-metal-polluted soils: screening for new accumulator plants in Angouran mine (Iran) and evaluation of removal ability.
Heavy metal pollution is a worldwide problem. Phytoremediation is an effective and low-cost interesting technology. This study was conducted in a dried waste pool of a lead and zinc mine in Angouran (Iran) to find accumulator plant(s). Concentrations of heavy metals were determined both in the soil and the plants that were grown in the mine and out of mine. The concentration of total Cu, Fe, Zn, Pb and Ni in the mine area were higher than the control soil. The results showed that five dominant vegetations namely Amaranthus retroflexus, Polygonum aviculare, Gundelia tournefortii, Noea mucronata and Scariola orientalis accumulated heavy metals. Based on the results, it was concluded that N. mucronata is the best accumulator for Pb, Zn, Cu, Cd and Ni, but the best Fe accumulator is A. retroflexus. Phytoremediation ability of N. mucronata was evaluated in experimental pots. The study showed that the amounts of heavy metals were decreased in polluted soils during experiments. The accumulation of metals in the root, leave and shoot portions of N. mucronata varied significantly but all the concentrations were more than natural soils. The results indicated that N. mucronata is an effective accumulator plant for phytoremediation of heavy-metals-polluted soils.


Characterization of a monoclonal anti-idiotypic antibody that mimics cyclosporine A in a single binding system.
BALB/c mice were immunized with a mixture of two anti-cyclosporine (CsA) mAb, H4 1.3 and D3 1.3, which recognize CsA amino acid residues reported to be important for its biologic activity and for its interaction with a CsA-binding protein, cyclophilin. A syngeneic anti-Id mAb, P43E, an IgG1 kappa, was generated. P43E bound to F(ab)'2 fragments of H4 1.3 in an ELISA and showed a dose-dependent inhibition of CsA binding to H4 1.3 and D3 1.3 in ELISA and RIA. The anti-Id antibody could be purified on an affinity column of H4 1.3/D3 1.3, and its binding to H4 1.3 could be inhibited by CsA. Dissociation kinetics and Scatchard analyses of P43E binding to H4 1.3 supported a reciprocal competitive inhibition mechanism for anti-Id binding, excluding a steric hindrance mechanism. P43E did not bind to several other anti-CsA mAb, a rabbit polyclonal anti-CsA antibody preparation, or cyclophilin. It is, therefore, a mimic of CsA but restricted to a single binding system. Our results are in agreement with the epitope specificities of the antibodies, X-ray and electron microscopic analysis of idiotope-anti-idiotope interactions, and recent nuclear magnetic resonance spectrometry studies of a CsA-cyclophilin complex and have implications with respect to the bioeffective epitope of CsA.


Agrochemical lead optimization by scaffold hopping.
Scaffold hopping, the exchange of a specific portion of a potential active ingredient with another substructure with the aim of finding isofunctional molecular structures with significantly different molecular backbones, often offers the chance in lead discovery or optimization to mitigate problems related to toxicity, intellectual property, and insufficient potency or stability. Scaffold hopping tools such as isosteric ring replacement including 1,3 nitrogen shift and cyclic imine-amide isosterism, but also ring opening and ring closure approaches, functional group isosterism, reversion of functional groups, chain shortening, chain lengthening, and scaffolds delivered by natural products, have become a permanent fixture of the innovation and optimization process in crop protection research. Their appropriate use will be explained through examples of success stories in the field of agrochemistry. Analogies to, but also differences from, the main categories of scaffold hopping in medicinal drug discovery are discussed. © 2017 Society of Chemical Industry.


A liquid biopsy assay for identifying early-stage hepatocellular carcinoma in asymptomatic HBsAg-seropositive individuals.
Biannual screening of hepatocellular carcinoma (HCC) by ultrasonography and serum α-fetoprotein has been proposed to the HBsAg-seropositive individuals. The widespread application to all of them was restricted due to limited acceptability of resource and anxiety-producing procedures. We recently developed a novel liquid biopsy assay to identify HCC cases in asymptomatic HBsAg-positive individuals.


Cranial pole nephrectomy in the pig model: anatomic analysis of arterial injuries in tridimensional endocasts.
To assess the intrarenal arteries injuries after cranial pole nephrectomy in a pig model to compare these findings with those in humans. Polyester resin was injected through the ureter and the renal artery to make three-dimensional casts of 61 pig kidneys. The cranial pole of the kidneys was sectioned at four different sites before the solidification of the resin, and the casts were examined for arterial damage. Section performed through the hilus (15 kidneys): The cranial division of the renal artery was sectioned in two (13.33%) cases, the ventral branch of the cranial division of the renal artery was sectioned in 13 (86.7%) cases, and the dorsal branch of the cranial division of the renal artery was sectioned in 11 (73.34%) cases. Section at 0.5 cm cranial to the hilus (16 kidneys): The cranial division of the renal artery was sectioned in 1 (6.25%) case, the ventral branch of the cranial division of the renal artery was sectioned in 14 (87.5%) cases, and the dorsal branch of the cranial division of the renal artery was sectioned in 13 (81.25%) cases. Section at 1.0 cm cranial to the hilus (15 kidneys): The ventral branch of the cranial division of the renal artery was sectioned in five (33.33%) cases, and the dorsal branch of the cranial division of the renal artery was injured in five (33.33%) cases. Section at 1.5 cm cranial to the hilus (15 kidneys): No lesions were found in the main arteries, only in the interlobular branches. As previously demonstrated in humans, sections at 1.0 cm or more cranially to the hilus in pigs also showed a significant decrease in damage to the major intrarenal arteries. Therefore, as regards arterial damage, the pig kidney is a useful model for partial nephrectomy in the cranial (upper) pole.


Fluorescent particle image velocimetry: application to flow measurement in refractive index-matched porous media.
This paper presents results in which particle image velocimetry (PIV) is used in conjunction with refractive index matching to measure fluid flow velocities within complex, multiphase systems. This application required the adaptation of PIV for use with fluorescent, rather than scattering, seed particles; we refer to the technique as fluorescent PIV (FPIV). We applied index-matched FPIV to the measurement of low flow velocities (tens of microns per second) at high spatial resolution (tens of microns) in a porous medium. We produced clear images of flowing particles in heterogeneous porous media and obtained reliable velocity vectors by a point-by-point interrogation of these images. We also found evidence of the intrapore mixing of porous media flow.


The molecular basis of bone mechanotransduction.
The skeleton has the ability to perfectly adapt to external forces of the operating environment, by altering its morphology and metabolism in order to meet different needs. This unique adaptive capacity of the skeleton creates an interesting range of biological questions concerning the perception of mechanical or other kinds of signals, the type of receptor, and the molecular pathways involved in this adaptation. Studies of the characteristics of the cellular engineering provide a host of new information that confers to osteocytes the role of the protagonist in the perception and regulation of mechanical effects on the skeleton. The identity of mechanoreceptors is manifold and concerns ion channels, integrins, cell membrane, the cytoskeleton, and other systems. A similar multiplicity characterizes the intracellular signaling. This review describes recent data concerning the outward force reception systems and intracellular transduction pathways of information transfer leading to the continuous adaptation of bone tissue. Increased appreciation of the importance of the mechanical environment in regulating and determining the effectiveness of structural adjustment of the skeleton defines new horizons for the discovery of novel therapeutic approaches to diseases associated with bone loss.