Retrieval analysis of metal and ceramic femoral heads on a single CoCr stem design.
The use of ceramic femoral heads in total hip arthroplasty (THA) has increased due to their proven low bearing wear characteristics. Ceramic femoral heads are also thought to reduce wear and corrosion at the head-stem junction with titanium (Ti) stems when compared with metal heads. We sought to evaluate taper damage of ceramic compared with metal heads when paired with cobalt chromium (CoCr) alloy stems in a single stem design. This retrieval study involved 48 total hip arthroplasties (THAs) with CoCr V40 trunnions paired with either CoCr (n = 21) or ceramic (n = 27) heads. The taper junction of all hips was evaluated for fretting/corrosion damage and volumetric material loss using a roundness-measuring machine. We used linear regression analysis to investigate taper damage differences after adjusting for potential confounding variables. We measured median taper material loss rates of 0.210 mm3/year (0.030 to 0.448) for the metal head group and 0.084 mm3/year (0.059 to 0.108) for the ceramic group. The difference was not significant (p = 0.58). Moreover, no significant correlation between material loss and implant or patient factors (p > 0.05) was found. Metal heads did not increase taper damage on CoCr trunnions compared with ceramic heads from the same hip design. The amount of material released at the taper junctions was very low when compared with available data regarding CoCr/Ti coupling in metal-on-metal bearings.Cite this article: A. Di Laura, H. Hothi, J. Henckel, I. Swiatkowska, M. H. L. Liow, Y-M. Kwon, J. A. Skinner, A. J. Hart. Retrieval analysis of metal and ceramic femoral heads on a single CoCr stem design. Bone Joint Res 2017;6:-350. DOI: 10.1302/2046-3758.65.BJR-2016-0325.R1.


Theoretical analysis of G6P production and simultaneous ATP regeneration by conjugated enzymes in an ultrafiltration hollow-fiber reactor.
The performance of an ultrafiltration hollow-fiber reactor, in which the enzymatic synthesis of glucose 6-phosphate from glucose and cofactor ATP and the enzymatic regeneration of ATP from ADP and acetyl phosphate are performed simultaneously, was analyzed theoretically. A simple analytical model in which the liquid flowing in the fiber tubes is assumed to be plug flow, and the radial concentration gradients in the tube and shell sides are both neglected, could simulate the reactor performance with satisfactory accuracy. The simulation elucidated the effects of the reactor configurations and various operational conditions on glucose conversion, ATP recycle number, and space-time yield. If the fiber tubes, through which the permeability of the relevant components such as substrates is high, were packed as much as possible in the reactor, good reactor performance could be expected. Furthermore, with a sufficiently high enzyme concentration, low ATP concentration in the feed solution, and appropriate space velocity, good space-time yield with high glucose conversion and with very high ATP recycle number is theoretically possible.


The Picornaviridae Family: Knowledge Gaps, Animal Models, Countermeasures, and Prototype Pathogens.
Picornaviruses are nonenveloped particles with a single-stranded RNA genome of positive polarity. This virus family includes poliovirus, hepatitis A virus, rhinoviruses, and Coxsackieviruses. Picornaviruses are common human pathogens, and infection can result in a spectrum of serious illnesses, including acute flaccid myelitis, severe respiratory complications, and hand-foot-mouth disease. Despite research on poliovirus establishing many fundamental principles of RNA virus biology and the first transgenic animal model of disease for infection by a human virus, picornaviruses are understudied. Existing knowledge gaps include, identification of molecules required for virus entry, understanding cellular and humoral immune responses elicited during virus infection, and establishment of immune-competent animal models of virus pathogenesis. Such knowledge is necessary for development of pan-picornavirus countermeasures. Defining enterovirus A71 and D68, human rhinovirus C, and echoviruses 29 as prototype pathogens of this virus family may provide insight into picornavirus biology needed to establish public health strategies necessary for pandemic preparedness.


Anatomy and histopathology of the human lacrimal gland.
To review the anatomy and histopathologic changes of the human main lacrimal gland. Samples of lacrimal gland including palpebral lobes and orbital lobes were taken in autopsies, and the relationship between histopathologic changes and age and sex, as well as histopathologic differences between palpebral and orbital lobes of the lacrimal gland, were studied using light microscopy. Various histopathologic changes were observed in the human main lacrimal gland as follows: acinar atrophy; periacinar fibrosis; periductal fibrosis; interlobular ductal dilatation; interlobular ductal proliferation; lymphocytic infiltration; and fatty infiltration. Several histopathologic differences exist between the palpebral and orbital lobes. There were statistically significant correlations between age and diffuse fibrosis, diffuse atrophy, and periductal fibrosis in the orbital lobes of women. Diffuse fibrosis and diffuse atrophy in orbital lobes were more frequently observed in women than in men. It is speculated that periductal fibrosis is related to a decrease of tear flow with age and that interlobular ductal dilatation in palpebral lobes may be caused by stenosis of the excretory duct in conjunctival fornix. However, the mechanisms of these histopathologic changes in the human main lacrimal gland are not yet clear.


The new oral anticoagulants in atrial fibrillation: once daily or twice daily?
The new anticoagulants (NOACs) tested for prevention or treatment of venous thromboembolism (VTE), stroke prevention in atrial fibrillation (AF), and acute coronary syndromes (ACS) differ in bioavailability, metabolism, route of excretion and interaction with other drugs, but have remarkably similar pharmacokinetics, with very similar half lives. However the choice of dosing regimens in different clinical conditions has been different for the various NOACs, and has been established on the basis of widely different considerations, including the clinical setting (venous versus arterial thrombosis), the indications (prophylaxis versus treatment), the likelihood of concomitant antiplatelet drugs, and marketing opportunities; these latter were based on the knowledge that patients' compliance is generally better with once daily than with twice daily dosing. Current prevailing wisdom is that peak plasma drug concentrations are important determinants of bleeding: since a fractioning of the total daily dose into a twice daily regimen reduces peak plasma drug concentrations compared with once daily dosing, this should maximize safety. However, recent pharmacokinetic analyses of a phase II study with edoxaban in AF found that bleeding, with the same daily dosing, was less frequent with once daily dosing than with twice daily dosing, and correlated - better than other pharmacokinetic parameters - through drug concentrations. Higher rates of bleeding have been also reported with the twice daily versus once daily dosing of darexaban in a phase II study in ACS. These results may lead to a rethinking on the pathophysiology of bleeding in the setting of anticoagulation.


A Simple Drain Current Model for MOS Transistors with the Lorentz Force Effect.
A novel concept of drain current modelling in rectangular normal MOS transistors with the Lorentz force has been proposed for the first time. The single-drain MOS transistor is qualified as a magnetic sensor. To create the Lorentz force, a DC loop current is applied through an on-chip metal loop around the device, and the relation between the applied loop current and the created magnetic field is assumed to be linear in nature. The drain current of the MOS transistor is reduced with the applied Lorentz force from both directions. This change in the drain current is ascribed to a change in mobility in the strong inversion region, and a change in mobility of around 4.45% is observed. To model this change, a set of novel drain current equations, under the Lorentz force, for the strong inversion region has been proposed. A satisfactory agreement of an average error of less than 2% between the measured and the calculated drain currents under the magnetic field created by an on-chip metal loop is achieved.


NHR-176 regulates cyp-35d1 to control hydroxylation-dependent metabolism of thiabendazole in Caenorhabditis elegans.
Knowledge of how drugs are metabolized and excreted is an essential component of understanding their fate within and among target and non-target organisms. Thiabendazole (TBZ) was the first benzimidazole (BZ) to be commercially available and remains one of the most important anthelmintic drugs for medical and veterinary use. We have characterized how Caenorhabditis elegans metabolizes and excretes TBZ. We have shown that TBZ directly binds to the nuclear hormone receptor (NHR)-176 and that this receptor is required for the induction by TBZ of the cytochrome P450 (CYP) encoded by cyp-35d1. Further, RNAi inhibition of cyp-35d1 in animals exposed to TBZ causes a reduction in the quantity of a hydroxylated TBZ metabolite and its glucose conjugate that is detected in C. elegans tissue by HPLC. This final metabolite is unique to nematodes and we also identify two P-glycoproteins (PGPs) necessary for its excretion. Finally, we have shown that inhibiting the metabolism we describe increases the susceptibility of C. elegans to TBZ in wild-type and in resistant genetic backgrounds.


Imaging of hepatocellular carcinoma and image guided therapies - how we do it.
Treatment options for hepatocellular carcinoma have evolved over recent years. Interventional radiologists and surgeons can offer curative treatments for early stage tumours, and locoregional therapies can be provided resulting in longer survival times. Early diagnosis with screening ultrasound is the key. CT and MRI are used to characterize lesions and determine the extent of tumour burden. Imaging techniques are discussed in this article as the correct imaging protocols are essential to optimise successful detection and characterisation. After treatment it is important to establish regular imaging follow up with CT or MRI as local residual disease can be easily treated, and recurrence elsewhere in the liver is common.


Repair and reconstruction of rotatory instability of the knee.
We studied the results of treatment in 110 of 129 consecutive patients who had knee instability for which they underwent reconstruction of the knee ligaments at the Mayo Clinic. Thirty-one patients underwent different types of extraarticular reconstruction. Nine (29%) had recurrence of the knee giving way, and 11 (36%) had objective signs of instability on examination. Fifty-five patients underwent combined extraarticular and intraarticular reconstruction with either the Lam-Jones patellar tendon (PT) procedure (21 knees) or the Zarins-Rowe semitendinosus and iliotibial band (ST & ITB) procedure (34 knees). Only two knees (10%) with PT procedure and three knees (9%) with ST & ITB procedures continued to have giving way. Three patients in each group had recurrence of instability. Twenty-four knees with acute instability had either primary repair (17 knees) or primary reconstruction with ST & ITB procedures (7 knees). The results in these knees were superior to the results in the knees reconstructed for chronic instability. On the basis of our 2 year results, we believe that a combined intraarticular and extraarticular reconstruction is the procedure of choice in chronic knee instability and is a useful procedure in acute knee instability with irreparable tears of the anterior cruciate ligament.


Enhancement of the finite-frequency superfluid response in the pseudogap regime of strongly disordered superconducting films.
The persistence of a soft gap in the density of states above the superconducting transition temperature Tc, the pseudogap, has long been thought to be a hallmark of unconventional high-temperature superconductors. However, in the last few years this paradigm has been strongly revised by increasing experimental evidence for the emergence of a pseudogap state in strongly-disordered conventional superconductors. Nonetheless, the nature of this state, probed primarily through scanning tunneling spectroscopy (STS) measurements, remains partly elusive. Here we show that the dynamic response above Tc, obtained from the complex ac conductivity, is highly modified in the pseudogap regime of strongly disordered NbN films. Below the pseudogap temperature, T*, the superfluid stiffness acquires a strong frequency dependence associated with a marked slowing down of critical fluctuations. When translated into the length-scale of fluctuations, our results suggest a scenario of thermal phase fluctuations between superconducting domains in a strongly disordered s-wave superconductor.


Antipneumococcal activities of a ketolide (HMR 3647), a streptogramin (quinupristin-dalfopristin), a macrolide (erythromycin), and a lincosamide (clindamycin).
Four different compounds belonging to the macrolide-lincosamide-streptogramin B (MLSb) class of antimicrobial agents were tested against 611 Streptococcus pneumoniae strains. The ketolide (HMR 3647, previously RU66647) and the streptogramin (quinupristin-dalfopristin) were both active against pneumococci with high-level MLSb resistance (clindamycin-resistant strains) as well as those with low-level macrolide resistance (clindamycin-susceptible strains).


Carbonic anhydrase to boost CO2 sequestration: Improving carbon capture utilization and storage (CCUS).
CO2 Capture Utilization and Storage (CCUS) is a fundamental strategy to mitigate climate change, and carbon sequestration, through absorption, can be one of the solutions to achieving this goal. In nature, carbonic anhydrase (CA) catalyzes the CO2 hydration to bicarbonates. Targeting the development of novel biotechnological routes which can compete with traditional CO2 absorption methods, CA utilization has presented a potential to expand as a promising catalyst for CCUS applications. Driven by this feature, the search for novel CAs as biocatalysts and the utilization of enzyme improvement techniques, such as protein engineering and immobilization methods, has resulted in suitable variants able to catalyze CO2 absorption at relevant industrial conditions. Limitations related to enzyme recovery and recyclability are still a concern in the field, affecting cost efficiency. Under different absorption approaches, CA enhances both kinetics and CO2 absorption yields, besides reduced energy consumption. However, efforts directed to process optimization and demonstrative plants are still limited. A recent topic with great potential for development is the CA utilization in accelerated weathering, where industrial residues could be re-purposed towards becoming carbon sequestrating agents. Furthermore, research of new solvents has identified potential candidates for integration with CA in CO2 capture, and through techno-economic assessments, CA can be a path to increase the competitiveness of alternative CO2 absorption systems, offering lower environmental costs. This review provides a favorable scenario combining the enzyme and CO2 capture, with possibilities in reaching an industrial-like stage in the future.


Influence of socioprofessional determinants on teachers' mental well-being.
Aims. To assess the influence of socio-professional factors on mental health of teachers at primary and secondary schools. Materials and Methods. It's a cross-sectional study, lasted 3 months of the year 2014. This study involved a representative sample of teachers working in public schools. Data collection was based on a survey sheet prepared beforehand and describing socio-demographic and occupational characteristics of the participants. Mental health was assessed by the GHQ 30 score in its validated version in Arabic. Results. Study population was composed of 255 teachers with a participation rate of 78.43%. This population was characterized by a slight female predominance (57.5%) with a sex ratio of 0.73. The mean age was 43.54 ± 8.9 years. Of the responding teachers, 17% felt that their profession was poorly perceived by the society. More than half of participants were satisfied with their profession (68.8%). Relational constraints with parents were reported by 50.5% of teachers. Seventy-one teachers reported having problem of indiscipline in class. The mean GHQ score was 7.21 ± 6.24. Teachers' psychological health deterioration was significantly correlated with smoking (p = 0.03, OR = 0.2, IC = [0.05-0.9]) , pathological antecedents (p = 0.02, OR = 3.6, IC = [1.1-10]), feeling guilty toward pupils passivity (p = 0.01, OR = 3.8, IC = [1.3-10]), to professional seniority (p = 0.008, OR = 0.2, IC = [0.06-0.6], to the image referred back by the society (p = 0.005, OR = 4.9, IC = [1.6-15]), to emotional exhaustion and personal satisfaction (p = 0.00, OR = 12.7, IC = [3.4-47] ). Conclusion. Acting on these factors through a collective preventive approach headed by the Ministry of Education is necessary to reduce the rate of psychological distress among teachers and therefore improve the quality of teaching.


Automating the drug scheduling of cancer chemotherapy via evolutionary computation.
This paper presents the optimal control of drug scheduling in cancer chemotherapy using a distributed evolutionary computing software. Unlike conventional methods that often require gradient information or hybridization of different approaches in drug scheduling, the proposed evolutionary optimization methodology is simple and capable of automatically finding the near-optimal solutions for complex cancer chemotherapy problems. It is shown that different number of variable pairs in evolutionary representation for drug scheduling can be easily implemented via the software, since the computational workload is shared and distributed among multiple computers over the Internet. Simulation results show that the proposed evolutionary approach produces excellent control of drug scheduling in cancer chemotherapy, which are competitive or equivalent to the best solutions published in literature.


Distribution of Scirtothrips dorsalis (Thysanoptera: Thripidae) cryptic species complex in the United States and reproductive host assessment of its dominant member.
Chilli thrips, Scirtothrips dorsalis Hood, is a cryptic species complex of at least 9 species, 2 of which (South Asia 1 and East Asia 1) have been confirmed damaging >50 plant taxa in the United States. To develop a knowledge-based management program for this pest in the United States, the objectives of the study were to (i) survey for S. dorsalis species complex in the suspected regions and (ii) assess the reproductive hosts of the predominant member available. Thrips samples received from collaborators were subjected to morpholo-molecular characterization. Of the 101 thrips populations received across the United States between 2015 and 2021, 71 populations were confirmed as S. dorsalis, with ~25% further identified as East Asia 1, compared with ~41% identified as South Asia 1, suggesting the latter species is more prevalent in the US. East Asia 1 was primarily found in samples collected from Hydrangea sp. (95%) in Massachusetts, New York, and Pennsylvania, indicating geographic range expansion in the Northeast and successful overwintering in areas with hard freezes. While assessing the host range of South Asia 1 (dominant species), 62 plant taxa were evaluated under greenhouse conditions. Among these, 40 feeding and reproductive hosts were confirmed in Florida. We also found 18 new reproductive hosts and 3 feeding hosts of S. dorsalis, which were not previously reported in the literature. The results provide insight into the increasing host range and expanded geographical distribution of S. dorsalis species and will enable the development of a species-specific monitoring and management program.


Expression dynamics of RpoS/Crl-dependent genes in Escherichia coli.
The alternative sigma factor RpoS is a central regulator of the stress response in many Proteobacteria, acting both during exponential growth and in stationary phase. The small protein Crl increases the interaction between RpoS and RNA polymerase and thereby activates certain RpoS-dependent promoters. However, the growth-phase dependence of the interaction of Crl with different forms of polymerase remains unknown. We use 41 GFP transcriptional fusions to study the dynamics of gene regulation by RpoS and Crl during growth transition from exponential to stationary phase in Escherichia coli. We confirm that RpoS can regulate gene expression in exponential phase, both positively and negatively. Crl slightly stimulates transcription by RpoS in exponential phase and controls a subset of RpoS-dependent genes in stationary phase. Growth temperature strongly affects induction of specific promoters by RpoS, whereas its impact on gene regulation by Crl is much less significant. In addition, we identify five new genes regulated by Crl (ada, cbpA, glgS, sodC and flgM) and demonstrate that Crl improves promoter binding and opening by RpoS-containing RNA polymerase at the hdeA promoter. Our study also shows that Crl is a cognate enhancer of RpoS activity under different growth conditions, since its deletion has no effect on genes transcribed by other sigma factors.


[Uterine smooth muscle tumors--determination of clinical behavior and classification].
The establishment of the clinical behavior of uterine smooth muscle tumors /USMT/ is an essential stage of modern diagnostics. There are significant differences in the criteria determining the malignant potential of smooth muscle gynecological tumors. Generally USMT generating diagnostic problems are classified into: clinically benign tumors; clinically malignant tumors with benign morphological features; smooth muscle tumors of uncertain malignant potential (SMTUMP) and lesions whose smooth muscle differentiation is not obvious. The knowledge in this area is essential for an adequate therapeutic approach.


Conduction velocity in the proximal segments of a motor nerve in the Guillain-Barré syndrome.
Conduction velocity from spinal cord to axilla (estimated using the F wave) has been compared with conduction velocity from axilla to wrist (measured in the conventional manner) in the motor fibres of the ulnar nerve in 17 controls subjects and in 11 patients with the Guillain-Barré syndrome (GBS). In the patients with GBS the conduction velocity was, in general reduced to a similar extent in both the proximal and the distal portions of the motor fibres, suggesting that the disease process is usually diffuse. In two patients, however, the conduction velocity in the proximal segment was disproportionally reduced and in one of these the conduction velocity in the distal segment was normal. It is concluded that the estimation of conduction velocity in the proximal segments of motor nerves may be of value in the assessment of patients with GBS.


Activation of Lyt-2+ (CD8+) and L3T4+ (CD4+) T cell subsets by anti-receptor antibody.
The mAb F23.1, specific for V beta 8-related determinants on the TCR, was used to study the requirements for TCR cross-linking and for accessory cells (AC) in the induction of proliferation or IL-2 responsiveness in L3T4+ (CD4+) and Lyt-2+ (CD8+) T cells. T cells were exposed in vitro to soluble native F23.1 antibody, to heteroconjugates composed of the Fab fragments of F23.1 linked to Fab fragments of antibodies specific for Ia determinants on AC, or to F23.1 immobilized on an insoluble matrix. Soluble F23.1 antibody-induced proliferation in naive T cells only in the presence of both AC and exogenous IL-2, and these responses were confined to Lyt-2+ T cells. In contrast, heteroconjugates capable of crosslinking F23.1+ TCR to AC surface Ia determinants were capable of inducing proliferation in both L3T4+ and Lyt-2+ T cells in the absence of added lymphokine. Moreover, binding to and presumably multi-valent crosslinking of the TCR by immobilized F23.1 was sufficient to induce proliferation in both Lyt-2+ and L3T4+ T cells in the absence of AC or exogenous IL-2. Further, it was found that the conditions necessary for T cell growth factor secretion paralleled closely those required for induction of T cell proliferation in the absence of added lymphokine, suggesting that production of endogenous lymphokine might be the limiting process for triggering of T cell proliferation. Taken together, these findings suggest that under optimal conditions of TCR cross-linking, TCR occupancy and cross-linking is sufficient to deliver all of the signals necessary to initiate proliferation in naive populations of both L3T4+ and Lyt-2+ T cells. However, when conditions for TCR signaling are suboptimal, as may be the case for normal Ag-mediated stimulation, a role for second signals delivered by AC or exogenous lymphokines can become critical for T cell activation.


The organisation of nurse staffing in intensive care units: A qualitative study.
To examine the organisation of the nursing workforce in intensive care units and identify factors that influence how the workforce operates. Pre-pandemic UK survey data show that up to 60% of intensive care units did not meet locally agreed staffing numbers and 40% of ICUs were closing beds at least once a week because of workforce shortages, specifically nursing. Nurse staffing in intensive care is based on the assumption that sicker patients need more nursing resource than those recovering from critical illness. These standards are based on historical working, and expert professional consensus, deemed the weakest form of evidence. Focus groups with intensive care health care professionals (n = 52 participants) and individual interviews with critical care network leads and policy leads (n = 14 participants) in England between December 2019 and July 2020. Data were analysed using framework analysis. Three themes were identified: the constraining or enabling nature of intensive care and hospital structures; whole team processes to mitigate nurse staffing shortfalls; and the impact of nurse staffing on patient, staff and intensive care flow outcomes. Staff made decisions about staffing throughout a shift and were influenced by a combination of factors illuminated in the three themes. Whilst nurse:patient ratios were clearly used to set the nursing establishment, it was clear that rostering and allocation/re-allocation during a shift took into account many other factors, such as patient and family nursing needs, staff well-being, intensive care layout and the experience, and availability, of other members of the multi-professional team. This has important implications for future planning for intensive care nurse staffing and highlights important factors to be accounted for in future research studies. In order to safeguard patient and staff safety, factors such as the ICU layout need to be considered in staffing decisions and the local business case for nurse staffing needs to reflect these factors. Patient safety in intensive care may not be best served by a blanket 'ratio' approach to nurse staffing, intended to apply uniformly across health services.


A Comparison between Clinical and Metabolic Features of Renal Calyceal Microlithiasis and Overt Urolithiasis in Different Pediatric Age Groups.
This study assesses the differences in the presentations, complications and metabolic abnormalities of children with renal calyceal microlithiasis (RCM) and overt urolithiasis in different pediatric ages. A total of 465 children with urolithiasis were investigated retrospectively. Patients were categorized based on their ages to infancy, early childhood, middle childhood and adolescence. When the hyperechogenic spots on ultrasound imaging were <3 mm, they were considered RCM, and if they were ≥3 mm, they were considered overt urolithiasis. Metabolic abnormalities were detected in 71%; hyperuricosuria in infants, hyperoxaluria in younger children and hypocitraturia in older children were the most common metabolic abnormalities. Hypercalciuria was the only metabolic abnormality that was significantly associated with overt urolithiasis in all pediatric ages (OR 2.25, 95% CI 1.21-4.19). The clinical presentations were not significantly different between RCM and overt urolithiasis; however, complications such as urinary tract infection was significantly higher with overt urolithiasis in infancy (p = 0.01), early childhood (p = 0.02), middle childhood (p = 0.007) and adolescence (p = 0.01). Also, growth retardation was significantly higher with overt urolithiasis in infancy and early childhood (p = 0.02). Most children with urolithiasis have underlying urinary metabolic abnormalities that differ according to the child's age. Despite these differences, hypercalciuria is significantly associated with overt urolithiasis in all pediatric ages. Clinical and laboratory features cannot differentiate RCM and overt urolithiasis; however, complications are significantly higher with overt urolithiasis.


First MEPS/HPLC assay for the simultaneous determination of venlafaxine and O-desmethylvenlafaxine in human plasma.
A new high-performance liquid chromatography-fluorescence detection assay based on microextraction by packed sorbent as sample preparation approach is described to quantify venlafaxine (VEN) and its main metabolite [O-desmethylvenlafaxine (ODV)]in human plasma. Chromatographic separation of the target analytes (VEN and ODV) and internal standard (licarbazepine) was achieved in less than 6 min on a reverse-phase C18 column using isocratic elution. Calibration curves were linear in the ranges of 10-1000 ng ml(-1) for VEN and 20-1000 ng ml(-1) for ODV. The method was successfully applied to real plasma samples. This microextraction by packed sorbent/high-performance liquid chromatography-fluorescence detection assay offers a cost-effective tool that can be applied for therapeutic drug monitoring and also support other pharmacokinetic-based studies in humans.


Generation of one control and four iPSCs clones from patients with Emery-Dreifuss muscular dystrophy type 1.
Emery-Dreifuss muscular dystrophy type 1 (EDMD1) is a rare genetic disease caused by mutations in the EMD gene coding for a nuclear envelope protein emerin. We generated and characterized induced pluripotent stem cells (iPSCs) from two EDMD1 patients bearing a mutation c.del153C and from one healthy donor. That mutation leads to generation of premature STOP codon. Established iPSCs are very valuable tool for disease pathogenesis investigation and for the development of new therapeutic methods after differentiation to cardiac or muscle cells. Obtained iPSCs show the proper morphology, pluripotency markers expression, normal karyotype and potential to differentiate into three germ layers.


A NEW METHOD FOR ESTIMATING INCREASE IN RADIATION DOSE ASSOCIATED WITH IODINATED CONTRAST USE.
This work investigates the impact of iodinated contrast medium (ICM) on radiation dose in computed tomography (CT) scans using linear models established through a phantom study. Thermoluminescence dosemeters (TLDs) were calibrated using semi-conductor X-ray dosemeters. An electron density phantom, with a vial containing TLDs and different concentrations of iodinated blood, were scanned at different tube voltages. Irradiated TLD outputs were measured and absorbed dose to iodinated blood calculated. CT numbers (tissue attenuation as measured by Hounsfield units) were plotted against absorbed doses to obtain linear models. Data from 49 real patient scans were used to validate the linear models. At each X-ray energy, CT numbers were linearly correlated with the absorbed doses, that is with the increase of blood iodine concentration, the CT number increased and the absorbed dose increased accordingly. ICM can cause an increase of organ dose; the average dose increases were 31.8 ± 8.9% for thyroid, 37.1 ± 9.2% for cardiac muscle, 77.7 ± 14.0% for cardiac chamber, 7.1 ± 2.3% for breast, 26.1 ± 7.3% for liver, 39.8 ± 11.8% for spleen, 96.3 ± 12.2% for renal cortex and 82.4 ± 11.6% for medulla nephrica. ICM used in enhanced CT scan resulted in increased organ doses. Our models for estimating organ dose based on CT number were established by experiment and verified in clinical use.


PTX3 expression in the heart tissues of patients with myocardial infarction and infectious myocarditis.
The long pentraxin 3 is involved in innate resistance to pathogens, controlling inflammation and extracellular matrix remodeling. Moreover, pentraxin 3 plays a nonredundant role in the regulation of cardiac tissue damage in mice and, recently, it has been proposed as a new candidate marker for acute and chronic heart diseases. However, the actual localization and cellular sources of pentraxin 3 in ischemic and infectious cardiac pathology have not been carefully defined. In this study, using immunohistochemistry, we analyzed pentraxin 3 expression in the heart tissues of patients with acute myocardial infarction at different time points after the ischemic event. In addition, we studied the heart tissues of patients with infectious myocarditis (fungi, bacteria, and protozoa) and patients who died of noncardiac events with normal heart histology. In acute myocardial infarction cases, we observed pentraxin 3 localized within and around ischemic lesions. On the contrary, no pentraxin 3 was observed in normal heart areas. In early ischemic lesions, pentraxin 3 was localized primarily in granulocytes; in more advanced acute myocardial infarction, pentraxin 3 positivity was found in the interstitium and in the cytoplasm of macrophages and the endothelium, whereas most granulocytes did not express pentraxin 3, presumably as a consequence of degranulation. In infectious myocarditis, pentraxin 3 was present and localized within and around histological lesions, associated with macrophage, endothelial cell, and, more rarely, myocardiocyte and granulocyte positivities. As observed in acute myocardial infarction patients, no pentraxin 3 staining was found in normal heart areas. Thus, neutrophils are an early source of pentraxin 3 in acute myocardial infarction and presumably other inflammatory heart disorders. Subsequently, in acute myocardial infarction and infectious myocarditis, pentraxin 3 is produced by macrophages, the endothelium, and, to a lesser extent, myocardiocytes, and localized in the interstitium.


Impairment of hypoxia-induced angiogenesis by LDL involves a HIF-centered signaling network linking inflammatory TNFα and angiogenic VEGF.
Hypoxia inducible factors (HIFs) mediate angiogenesis via up-regulation of various pro-angiogenic factors (particularly VEGF) in response to hypoxia. Here, we report that hypoxia unexpectedly induced robust production of the pro-inflammatory factor TNFα by endothelial cells (ECs), suggesting an autocrine loop that in turn activated HIFs via an NF-κB-dependent process, resulting in production of VEGF and thereby promotion of angiogenesis. In contrast, low-density lipoprotein (LDL) prevented expression of HIFs in ECs exposed to either hypoxia or TNFα, while knockdown of either HIF-1α or HIF-2α strikingly attenuated hypoxia-induced production of VEGF by ECs as well as EC colony formation and tube formation. Significantly, LDL attenuated hypoxia-induced angiogenesis by disrupting the TNFα/NF-κB/HIF/VEGF signaling cascade via down-regulation of the TNF receptor TNF-R1, rather than TNFα itself, and multiple key components of both canonical and non-canonical NF-κB pathways. By doing so, LDL was able to either inhibit or down-regulate a wide spectrum of HIF-dependent pro-angiogenic downstream targets and signals. Together, these findings argue existence of a self-regulatory TNFα/NF-κB/HIF/VEGF signaling network in ECs, which mediates and fine-tones angiogenesis, at least in response to hypoxia. They also suggest that LDL impairs angiogenesis by disrupting this network, which might represent a novel mechanism underlying anti-angiogenic property of LDL.


Arsenic removal from groundwater and its safe containment in a rural environment: validation of a sustainable approach.
Of all the naturally occurring groundwater contaminants, arsenic is by far the most toxic. Any large-scale treatment strategy to remove arsenic from groundwater must take into consideration safe containment of the arsenic removed with no adverse ecological impact. Currently, 175 well-head community-based arsenic removal units are in operation in remote villages of the Indian subcontinent. Approximately 150,000 villagers collect arsenic-safe potable water everyday from these units. The continued safe operation of these units has amply demonstrated that use of regenerable arsenic-selective adsorbents is quite viable in remote locations. Upon exhaustion, the adsorbents are regenerated in a central facility by a few trained villagers and reused. The process of regeneration reduces the volume of disposable arsenic-laden solids by nearly 2 orders of magnitude. Finally, the arsenic-laden solids are contained on well-aerated coarse-sand filters with minimum arsenic leaching. This disposal technique is scientifically more appropriate than dumping arsenic-loaded adsorbents in the reducing environment of landfills as currently practiced in developed countries including the United States.


Substrate protection of immobilized glucose isomerase.
Using commercial immobilized glucose isomerase (SWETASE(R), Nagase Co.), the effect of substrate protection on enzyme deactivation has been studied in a batch manner. The data analysis was carried out based on Briggs-Haldane kinetics in which enzyme deactivation accompanying the protection of substrates was also considered. The protection factor was proposed to elucidate the dependence of the degree of substrate protection. The existence of the protection of glucose isomerase by the substrates has been verified experimentally. Also, the enzyme-substrate complex deactivates with a decay constant which is one-half that of the free enzyme. Theoretical analysis of enzyme deactivation with substrate protection offers an effective understanding which is essential for enzyme replacement and process optimization.


Prognostic significance of HER2 gene amplification according to stage of breast cancer.
It is well known that the amplification of the HER2 gene is closely associated with poor prognosis of breast cancer. However, there is controversy about the clinical significance of HER2 according to lymph node status in breast cancer. The aim of this study was to identify the differences in the prognostic significance of HER2 gene amplification according to the stages of breast cancer. We prepared a tissue array for fluorescence in situ hybridization (FISH) with breast cancer specimens from the surgery in 1994 to 1999. Total 338 cases of breast cancer were enrolled and the median follow-up period was 6.3 yr. The detection rates of HER2 gene amplification were as follows: 10.3% in stage I, 22.3% in stage II, and 43.8% in stage III. On survival analyses HER2-positive groups showed worse prognosis in stage III of breast cancer, but not in stage I or II. Multivariate analyses with a Cox-regression model also revealed that HER2 amplification was an independent prognostic factor only in stage III breast cancer. Regarding HER2 gene amplification as a prognostic factor of breast cancer, the clinical significance of the gene was found to be confined to advanced breast cancer.


Water transport in the nano-pore of the calcium silicate phase: reactivity, structure and dynamics.
Reactive force field molecular dynamics was utilized to simulate the reactivity, structure and dynamics of water molecules confined in calcium-silicate-hydrate (C-S-H) nano-pores of 4.5 nm width. Due to the highly reactive C-S-H surface, hydrolytic reactions occur in the solid-liquid interfacial zone, and partially surface adsorbed water molecules transforming into the Si-OH and Ca-OH groups are strongly embedded in the C-S-H structure. Due to the electronic charge difference, the silicate and calcium hydroxyl groups have binomial distributions of the dipolar moment and water orientation. While Ca-OH contributes to the Ow-downward orientation, the ONB atoms in the silicate chains prefer to accept H-bonds from the surface water molecules. Furthermore, the defective silicate chains and solvated Caw atoms near the surface contribute to the glassy nature of the surface water molecules, with large packing density, pronounced orientation preference, and distorted organization. The stable H-bonds connected with the Ca-OH and Si-OH groups also restrict the mobility of the surface water molecules. The significant reduction of the diffusion coefficient matches well with the experimental results obtained by NMR, QENS and PCFR techniques. Upon increasing the distance from the channel, the structural and dynamic behavior of the water molecules varies and gradually translates into bulk water properties at distances of 10-15 Å from the liquid-solid interface.


Common Genetic Variation Near Melatonin Receptor 1A Gene Linked to Job-Related Exhaustion in Shift Workers.
Tolerance to shift work varies; only some shift workers suffer from disturbed sleep, fatigue, and job-related exhaustion. Our aim was to explore molecular genetic risk factors for intolerance to shift work. We assessed intolerance to shift work with job-related exhaustion symptoms in shift workers using the emotional exhaustion subscale of the Maslach Burnout Inventory-General Survey, and carried out a genome-wide association study (GWAS) using Illumina's Human610-Quad BeadChip (n = 176). The most significant findings were further studied in three groups of Finnish shift workers (n = 577). We assessed methylation in blood cells with the Illumina HumanMethylation450K BeadChip, and examined gene expression levels in the publicly available eGWAS Mayo data. The second strongest signal identified in the GWAS (p = 2.3 × 10E-6) was replicated in two of the replication studies with p < .05 (p = 2.0 × 10E-4 when combining the replication studies) and indicated an association of job-related exhaustion in shift workers with rs12506228, located downstream of the melatonin receptor 1A gene (MTNR1A). The risk allele was also associated with reduced in silico gene expression levels of MTNR1A in brain tissue and suggestively associated with changes in DNA methylation in the 5' regulatory region of MTNR1A. These findings suggest that a variant near MTNR1A may be associated with job-related exhaustion in shift workers. The risk variant may exert its effect via epigenetic mechanisms, potentially leading to reduced melatonin signaling in the brain. These results could indicate a link between melatonin signaling, a key circadian regulatory mechanism, and tolerance to shift work.


[Preliminary experimental research on gene therapy for hemophilia A].
To accomplish a kind of therapeutic gene for hemophilia A, and observe the expression of human factor VIII (hF VIII) in vivo. Human clotting factor VIII cDNA with B-domain deleted (Delta760aa approximately 1639aa) was inserted into vector pRC/RSV to form pRC/RSV-hF VIII BD, which conjugated with in vivo liposome transfection reagent (DOTAP-Cholesterol) to accomplish a kind of therapeutic gene, pRC/RSV-hF VIII BD-DOTAP-Cholesterol. Mice were injected with pRC/RSV-hF VIII BD-DOTAP-Cholesterol i.m. and sacrificed 48 hours, 10 days, 20 days, 30 days, 40 days and 50 days later, respectively. Tissues such as heart, liver, spleen, lung, kidney and muscle were harvested, the distribution and transcription as well as expression of hF VIII BD cDNA were detected by means of PCR, RT-PCR and immunohistochemistry techniques. In addition, the antigen and antibody of hF VIII in plasma were measured. There was high expression of hF VIII in plasma and tissues at the 48(th) hour after injection. On day 10, antigen level of hF VIII in plasma reached its peak, 17.55 ng/ml, and gradually reduced later. The antibody of hF VIII in plasma emerged on day 10 after injection, and increased and gradually reached 37.06 U/ml on day 50 after injection. PCR, RT-PCR and immunohistochemistry showed that hF VIII BD cDNA and its transcription as well as expression existed in all kinds of tissues, and lasted longer in spleen, lungs and kidneys than in heart, liver and muscle. Therapeutic gene, pRC/RSV-hF VIII BD-DOTAP-Cholesterol, produced by combination of pRC/RSV-hF VIII BD and DOTAP-Cholesterol liposome can express human F VIII successfully in vivo, which lays an experimental foundation for curing hemophilia A by gene-drug in clinic.


Effect of acetate Ringer's solution with or without 5% dextrose administered intravenously to diarrheic calves.
The objectives of this study were to evaluate the effects of intravenous acetate Ringer's solution, with or without dextrose, on diarrheic calves with either experimentally induced or spontaneous diarrhea. In the experimental model, diarrhea was induced in nine healthy calves by administering cold milk (below 4°C) twice a day for 2 days. The calves were randomly assigned to the isotonic saline (ISS), acetated Ringer's (AR) or acetated Ringer's with 5% dextrose (ARD) groups, with three calves assigned to each group. The calves received 80 ml/kg of their designated solution, at a flow rate of 20 ml/kg/hr. Infusion of ISS, AR and ARD were all found to be safe and effective in increasing plasma volume. Intravenous (IV) infusion of ISS resulted in the acidification secondary to dilution, while AR and ARD infusion inhibited acidification. In addition, prevention of catabolism was observed only with IV infusion of ARD. Sixteen calves with spontaneous diarrhea were enrolled in the clinical study. The calves were randomly assigned to the AR or ARD groups, with eight calves being assigned to each group. The calves received 100 ml/kg of their designated solution, at a flow rate of 25 ml/kg/hr. Intravenous infusion of AR and ARD was found to be effective in increasing plasma volume and inhibiting acidification. Only infusion of ARD prevented catabolism, but it also led to hyperglycemia. Our results suggest that a solution containing dextrose may be beneficial for wasting diarrheic calves.


Pulmonary hypertension: epidemiology in different CKD stages and its association with cardiovascular morbidity.
Pulmonary hypertension (PH) was recently recognized as a common complication of end-stage renal disease (ESRD) that causes an increased risk of mortality. Epidemiological data for this disorder in earlier stages of chronic kidney disease (CKD) and its association with cardiovascular (CV) morbidity are scarce. We retrospectively analyzed 2,351 Chinese CKD patients with complete clinical records and echocardiography data between Jan 2008 and May 2012. The patients were divided into the following 6 groups: CKD Stages 1-4; Stage 5 for those not on or initiated on hemodialysis for <3 months; and Stage 5D for the patients undergoing hemodialysis for ≥3 months. The prevalence of PH and CV morbidity was investigated, and their association was evaluated with a logistic regression model. PH was detected in 426 patients (18.1%). Mild, moderate and severe PH was diagnosed in 12.1%, 4.9% and 1.1% of the patients, respectively. Severe PH was detected in CKD Stages 5 and 5D. CV morbidity was found in 645 patients (27.4%). Compared with the non-PH group, the PH group had a higher risk for cardiac disease but not for cerebrovascular disease risk. PH severity was associated with cardiac morbidity risk [odds ratio (95% CI) for mild PH: 1.79 (1.30-2.47); moderate PH: 2.75 (1.73-4.37); severe PH: 3.90 (1.46-10.42)]. Our study showed for the first time the epidemiology profile of PH across the spectrum of CKD. Mild-to-moderate PH occurs with more frequency in advanced CKD, and severe PH is scarce in non-ESRD CKD. PH in CKD is associated with cardiac but not cerebrovascular disease, with increasing cardiac morbidity seen with increasing PH severity. Evidence from prospective studies addressing PH in this population is needed to predict cardiac events.


The role of galectin-3 and galectin-3-binding protein in venous thrombosis.
Galectin-3-binding protein (gal3bp) and its receptor/ligand, galectin-3 (gal3), are secreted proteins that initiate signaling cascades in several diseases, and recent human proteomic data suggest they may play a role in venous thrombosis (VT). We hypothesized that gal3bp and gal3 may promote VT. Using a mouse stasis model of VT, we found that gal3bp and gal3 were localized on vein wall, red blood cells, platelets, and microparticles, whereas leukocytes expressed gal3 only. Gal3 was dramatically increased during early VT and gal3bp:gal3 colocalized in the leukocyte/endothelial cell interface, where leukocytes were partially attached to the vein wall. Thrombus size correlated with elevated gal3 and interleukin-6 (IL-6) vein wall levels. Recombinant gal3 promoted VT and increased vein wall IL-6 mRNA. Although recombinant gal3 restored the VT size in gal3(-/-) mice, it had no effect on IL6(-/-) mice, suggesting that gal3:gal3bp promotes VT through IL-6. Moreover, significantly fewer activated neutrophils were present in the gal3(-/-) vein walls. In a group of human patients, elevated circulating gal3bp correlated with acute VT. In conclusion, gal3bp:gal3 play a critical role in VT, likely via IL-6 and PMN-mediated thrombotic mechanisms, and may be a potential biomarker in human VT.


[Measuring coronary circulation using an inert gas method--a comparison of common indicator gases].
Validation studies of inert gas techniques are limited in number and usually have not included circumstances with marked heterogeneity of flow. This study was intended to investigate the validity of the method in experimental animals under various hemodynamic conditions by parallel application of helium, argon, krypton and xenon as indicators and by comparison with direct flow measurements. Gases were applied by single breath inhalation. In order to avoid the limitations of conventional methods arising from the systemic recirculation of tracer and from shortened measuring periods we used continuous mass spectrometric recording and numeric deconvolution of the dilution curves in arterial and coronary venous blood. When the transit times are evaluated by "stochastic" analysis and commonly used tissue/blood partition-coefficients (lambda He = 0.95, lambda Ar = 1.1) the helium and argon values are found in reasonable agreement with reference flows. The effects of a shortening of measurements that are based on single integrated samples (Argon method) are shown under control conditions, adenosin infusion and elevated ventricular filling pressure. With xenon (lambda Xe = 0.7) coronary blood flow above 100 ml/min X 100 g is underestimated by the "stochastic" and by the "initial slope technique"; parallel measurements with argon suggest that in the initial slope technique a lambda Xe between 0.8 and 0.9 might be more adequate.


Genetic Characterization of Serotypes A and Asia-1 Foot-and-mouth Disease Viruses in Balochistan, Pakistan, in 2011.
This study reports characterization of foot-and-mouth disease virus (FMDV) in samples collected from Balochistan, Pakistan. FMDV was detected by pan-FMDV real-time RT-PCR in 31 samples (epithelial and oral swabs) collected in 2011 from clinical suspect cases. Of these, 29 samples were serotyped by serotype-specific real-time RT-PCR assays and were confirmed by sequencing the VP1 coding region. Sixteen samples were found positive for serotype A and eight for serotype Asia-1, whereas five samples were found positive for both serotypes A and Asia-1. Two serotype A positive samples were found positive for two different strains of serotype A FMDV each. Phylogenetic analyses of serotype A FMDVs showed circulation of at least three different sublineages within the A-Iran05 lineage. These included two earlier reported sublineages, A-Iran05HER-10 and A-Iran05FAR-11 , and a new sublineage, designated here as A-Iran05BAL-11 . This shows that viruses belonging to the A-Iran05 lineage are continuously evolving in the region. Viruses belonging to the A-Iran05FAR-11 sublineage showed close identity with the viruses circulating in 2009 in Pakistan and Afghanistan. However, viruses belonging to the A-Iran05HER-10 detected in Balochistan, Pakistan, showed close identity with the viruses circulating in Kyrgyzstan, Iran and Kazakhstan in 2011 and 2012, showing that viruses responsible for outbreak in these countries have a common origin. Serotype Asia-1 FMDVs reported in this study all belonged to the earlier reported Group-VII (Sindh-08), which is currently a dominant strain in the West Eurasian region. Detection of two different serotypes of FMDV or/and two different strains of the same serotype in one animal/sample shows complexity in occurrence of FMD in the region.


Borrelia burgdorferi mutant lacking Osp: biological and immunological characterization.
All Borrelia burgdorferi sensu lato isolates characterized to date have one or a combination of several major outer surface proteins (Osps). Mutants of B. burgdorferi lacking Osps were selected with polyclonal or monoclonal antibodies at a frequency of 10(-6) to 10(-5). One mutant that lacked OspA, -B, -C, and -D was further characterized. It was distinguished from the OspA+B+ cells by its (i) autoaggregation and slower growth rate, (ii) decreased plating efficiency on solid medium, (iii) serum and complement sensitivity, and (iv) diminished capacity to adhere to human umbilical vein endothelial cells. The Osp-less mutant was unable to evoke a detectable immune response after intradermal live cell immunization even though mutant survived in mouse skin for the same duration as wild-type cells. Polyclonal mouse serum raised against Osp-less cells inhibited growth of the mutant but not of wild-type cells, an indication that other antigens are present on the surface of the Osp-less mutant. Two types of monoclonal antibodies (MAbs) with growth-inhibiting properties for mutant cells were identified. The first type bound to a 13-kDa surface protein of B. burgdorferi sensu stricto and of B. afzelii. The MIC of the Fab fragment of one MAb of this type was 0.2 micrograms/ml. The second type of MAb to the Osp-less mutant did not bind to B. burgdorferi components by Western blotting (immunoblotting) but did not bind to unfixed, viable cells in immunofluorescence and growth inhibition assays. These studies revealed possible functions Osp proteins in borrelias, specifically serum resistance, and indicated that in the absence of Osp proteins, other antigens are expressed or become accessible at the cell surface.


Predict disease progression from T-cell phenotypes in northern pig-tailed macaques (Macaca leonina) during SIVmac239 infection.
Macaca leonina (northern pig-tailed macaques, NPMs) have variable disease progression during SIVmac239 infection. In the present study, we analysed, for the first time, the correlations between T-cell phenotypes and disease progression in NPMs during SIVmac239 infection. In comparison to normal progressors (NPs), slow progressors (SPs) had lower chronic T-cell activation and exhaustion levels. In addition, SPs showed higher peripheral CD4+ T-cell count and CD4 : CD8 ratio, and lower plasma viral load than NPs. CD4+ T-cell count and CD4 : CD8 ratio decreased more sharply in NPs than in SPs. Furthermore, T cells in NPs were more highly differentiated, at least in acute infection, than in SPs. These results indicated that T-cell phenotypes were correlated with disease progression in SIVmac239-infected NPMs and these correlations may provide valuable guidance for the improvement of therapeutic strategies tested in NPMs.


[Tumors of the liver secondary to androgen therapy. Apropos of 2 cases in children].
The authors report 2 cases of hepatocellular tumour in children treated with anabolic androgens for aplastic anemia. In both cases, the presentation was by a picture of acute abdomen due to hemoperitoneum caused by tumour rupture. In the first case, there was multiple hepatic adenomas necessitating right hepatic lobectomy. The second infant had a single tumour of segment IV treated by simple excision of the tumour. It was a hepatocellular-carcinoma. Follow-up for one year after the initial operation showed no signs of recurrence in both infants. The review of the literature permitted us to find 48 other cases of hepatocellular tumour secondary to androgen therapy. In order of frequency, the hepatocellular-carcinoma is the most frequent and it is usually single; followed by the adenoma which is usually multiple. The other types of tumours are rare: focal nodular hyperplasia, angiosarcoma and cholangiocarcinoma. The hepatocellular-carcinoma and adenoma have some characteristic features: spontaneous regression may occur after withdrawing of androgens; the risk of rupture is important; their evolution is almost always favorable despite of a severe histopathological picture; the alpha-foeto-protein is nearly always negative; and the metastasis are exceptional. The hepatocellular-carcinomas associated with androgen therapy are probably just adenomas with marked dysplasia, but their long term malignant potential remain unknown. Except in case of rupture, surgical intervention should be postponed until the effect of discontinuing the hormonal therapy is assessed, because of the potential for spontaneous regression. The administration of antineoplastic chemotherapeutic agents should be reserved for the tumours showing evidence of malignancy.


[Pharmacology of adrenergic beta receptor blockaders].
Betablockers may be classified according to their cardio selectivity, intrinsic sympathomimetic action and direct vasodilating action. All beta blockers reduce renin plasma levels, the effect being inversely proportional to the intrinsic sympathomimetic property. The hypotensive effect is related more to vasodilation than to a decrease in cardiac output. The hypotensive action is mediated by presynaptic beta receptors which normally stimulate noradrenaline secretion by nerve endings. Adverse effects, interaction with other drugs, and effects on risk factors of beta blockers are also reviewed.


Base substitutions, length differences and DNA strand asymmetries in the human G gamma and A gamma fetal globin gene region.
We have studied differences arising subsequent to the 5 kilobase pair (kb) duplication that led to the human G gamma and A gamma fetal globin genes. The local occurrence of base substitutions in the duplicated 5 kb region correlates positively with the local AT base pair content. This correlation also occurs in two mouse beta-globin genes and in two mouse immunoglobulin genes. The relationship is valid for transcribed or nontranscribed DNA and for DNA that contains only coding sequences. Length differences in the fetal globin duplicated regions correlate positively with the occurrence of short direct repeats of greater than or equal 5 base pairs. Path analysis of the interrelationships of base composition, base substitutions, repeats and length differences provides an integrated view of the relative effects on chromosomal changes of these variables and of selection. The distributions along the chromosome of simple sequences and of base compositions show highly significant local asymmetries between the transcribed and nontranscribed strands of the DNA, which permit us to divide the fetal globin gene region into chromosomal domains. Comparable domains are present in DNA from other sources, including the mammalian viruses SV40 and polyoma virus strain A-2 in which some of the domains appear related to discrete functions.


Effect of capsaicin on breast cancer resistance protein (BCRP/Abcg2) and pharmacokinetics of probe substrates in rats.
Breast cancer resistance protein (BCRP/Abcg2 in human, Bcrp/Abcg2 in rat), a member of the ATP-binding cassette (ABC) transporter family, acts as an efflux pump for xenobiotics, with ability to transport various drugs out of cells. Capsaicin may have the potential to modulate the function of Bcrp transport. This study was to evaluate the effects of capsaicin on the pharmacokinetics of sulfasalazine, a Bcrp substrate, in rats and investigate the mechanism of this food-drug interaction.The rats were pre-treated with 5% carboxymethylcellulose sodium (vehicle), capsaicin (3, 8, 25 mg/kg) and cyclosporine A (10 mg/kg) by gastric gavage for 7 days. On day 7, blood, liver and intestine samples were collected after sulfasalazine administered. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to study the effects of capsaicin on the pharmacokinetics of sulfasalazine in rats. RT-PCR and western blotting were used to study the mechanism in biomolecules in rats, respectively.Compared with vehicle group, AUC0-∞ of sulfasalazine in rats were increased by 1.5-folds, 1.6-folds and 1.7-folds in 3, 8 and 25 mg/kg/d capsaicin pre-treated groups. At the same time, the CL/F in rats were decreased by 33%, 38% and 42% in the three groups. In addition, we found Bcrp mRNA levels and protein expressions in rat livers and intestines were decreased in 3, 8 and 25 mg/kg/d capsaicin-treated groups.Our study demonstrated that long-term ingestion of capsaicin significantly enhanced the AUC of sulfasalazine involved down-regulate Bcrp gene and protein expression in rat liver and intestine.


A Randomized Phase II Study of Axitinib as Maintenance Therapy After First-line Treatment for Metastatic Colorectal Cancer.
The aim of this study was to evaluate the efficacy and safety of maintenance therapy with axitinib versus placebo following induction therapy in patients with metastatic colorectal cancer (mCRC). In this double-blinded, phase II trial, patients with mCRC who had not progressed after 6 to 8 months of first-line chemotherapy were randomized to receive axitinib (5 mg twice a day) (arm A) or placebo (arm B). Forty-nine patients were included: 25 in arm A and 24 in arm B. The median follow-up was 26.07 months (95% confidence interval [CI], 18.44-31.73 months). Progression-free survival (PFS) rate at 6 months was 40.00% (95% CI, 21.28%-58.12%) in the axitinib arm versus 8.33% (95% CI, 1.44%-23.30%) in the placebo arm (P = .0141). The median PFS was statistically significantly longer in the axitinib group than in the placebo group (4.96 vs. 3.16 months; hazard ratio, 0.46; 95% CI, 0.25-0.86; P = .0116). Median overall survival was also longer in the axitinib arm but did not reach statistical significance (27.61 vs. 19.99 months; hazard ratio, 0.68; 95% CI, 0.31-1.48; P = .3279). Grade 3 to 4 treatment-related toxicities were experienced by 7 patients (28%) in cohort A and 1 patient (4%) in cohort B (P = .0488). The most frequent grade 3 to 4 treatment-related toxicities were hypertension, diarrhea, and asthenia. There were no toxic deaths. The study was prematurely closed because of slow recruitment. In our study, maintenance treatment with axitinib monotherapy showed a significant increase in PFS and a good safety profile. Axitinib should be further explored as a possible option for first-line chemotherapy maintenance treatment in patients with mCRC.


Model for community health nursing care: application to an integrated asthma intervention program.
The article describes the use of a model for community health nursing care applied to an integrated asthma intervention program in an inner-city context. Asthma is a chronic childhood disease with broad physical, social, and economic impact on children, families, and communities. Despite recent advances in asthma understanding and treatment, morbidity and mortality continue to rise. This model suggests ways to combine individual, family, school, and community interventions to enhance coordination and increase the impact of services. It outlines needs and opportunities for collegial collaboration between professional nurses in varied practice settings. Application of the model to the management of asthma in the urban setting demonstrates the potential to produce significant improvement in the management of conditions such as asthma and highlights the key role that school nurses play.


The Development of a Conceptual Framework for Providing Tailored Diabetes Care for Individuals Experiencing Homelessness: A Qualitative Study.
Homelessness results in barriers to effective diabetes self-management. Programs targeting individuals facing homelessness have refined strategies to address these barriers. We sought to develop a framework to characterize these strategies that could help multidisciplinary providers to better support these individuals. Semi-structured interviews were conducted with a purposive sample of health and social care providers working in diabetes or homelessness in five Canadian cities (n=96). Interview transcripts were analyzed through qualitative thematic analysis. Providers described three groups of approaches that enabled care for this population. Person-centered provider behaviours: This included tailoring care plans to accommodate individuals' situational constraints. Lower-barrier organizational structure: Providers developed specialized organizational processes to increase accessibility. Bridging to larger care systems: Strategies included providing access to support workers. Across diverse program structures, similar approaches are used to enhance diabetes care for individuals who are experiencing homelessness, highlighting tangible opportunities for mainstream services to better engage with this population.


Twisted vortex filaments in the three-dimensional complex Ginzburg-Landau equation.
The structure and dynamics of vortex filaments that form the cores of scroll waves in three-dimensional oscillatory media described by the complex Ginzburg-Landau equation are investigated. The study focuses on the role that twist plays in determining the bifurcation structure in various regions of the (alpha,beta) parameter space of this equation. As the degree of twist increases, initially straight filaments first undergo a Hopf bifurcation to helical filaments; further increase in the twist leads to a secondary Hopf bifurcation that results in supercoiled helices. In addition, localized states composed of superhelical segments interspersed with helical segments are found. If the twist is zero, zigzag filaments are found in certain regions of the parameter space. In very large systems disordered states comprising zigzag and helical segments with positive and negative senses exist. The behavior of vortex filaments in different regions of the parameter space is explored in some detail. In particular, an instability for nonzero twist near the alpha=beta line suggests the existence of a nonsaturating state that reduces the stability domain of straight filaments. The results are obtained through extensive simulations of the complex Ginzburg-Landau equation on large domains for long times, in conjunction with simulations on equivalent two-dimensional reductions of this equation and analytical considerations based on topological concepts.


The T Cell Response to the Contact Sensitizer Paraphenylenediamine Is Characterized by a Polyclonal Diverse Repertoire of Antigen-Specific Receptors.
Paraphenylenediamine (PPD) is a common component of hair dyes and black henna tattoos and can cause skin sensitization and allergic contact dermatitis (ACD). The cutaneous inflammatory reaction associated with ACD is driven by both CD4+ and CD8+ T cells. However, the characteristics of such responses with respect to clonal breadth and magnitude are poorly defined. In this study, we have characterized the in vitro recall response of peripheral blood T cells prepared from PPD-allergic individuals to a PPD-human serum albumin (HSA) conjugate (PPD-HSA). Quantitative high throughput sequencing was used to characterize the changes in the repertoire of T cell receptor (TCR) α and β genes after exposure to antigen in vitro. The PPD conjugate induced expansion of T cells carrying selected TCRs, with around 800 sequences (around 1%) being 8 or more times as abundant after culture than before. The expanded sequences showed strong skewing of V and J usage, consistent with an antigen-driven clonal expansion. The complementarity-determining region 3 sequences of the expanded TCRs could be grouped into several families of related amino acid sequence, but the overall diversity of the expanded sample was not much less than that of a random sample of the same size. The results suggest a model in which PPD-HSA conjugate stimulates a broad diversity of TCRs, with a wide range of stimulation strengths, which manifest as different degrees of in vitro expansion.


[Familial choroideremia--case report].
We present a case of familial choroideremia followed for several years in 3 successive generations and which represented a diagnostic challenge as the final diagnosis was provided only by genetic testing.


Diversity and patterns of interaction of an anuran-parasite network in a neotropical wetland.
We describe the diversity and structure of a host-parasite network of 11 anuran species and their helminth parasites in the Pantanal wetland, Brazil. Specifically, we investigate how the heterogeneous use of space by hosts changes parasite community diversity, and how the local pool of parasites exploits sympatric host species of different habits. We examined 229 anuran specimens, interacting with 32 helminth parasite taxa. Mixed effect models indicated the influence of anuran body size, but not habit, as a determinant of parasite species richness. Variation in parasite taxonomic diversity, however, was not significantly correlated with host size or habit. Parasite community composition was not correlated with host phylogeny, indicating no strong effect of the evolutionary relationships among anurans on the similarities in their parasite communities. Host-parasite network showed a nested and non-modular pattern of interaction, which is probably a result of the low host specificity observed for most helminths in this study. Overall, we found host body size was important in determining parasite community richness, whereas low parasite specificity was important to network structure.


A Retrospective Evaluation on Demographic, Phenomenological, and Comorbidity Features of Pediatric Obsessive-Compulsive Disorder.
The impacts of sex, age of onset, phenotype, and comorbidity on clinical features were explored in a large clinical sample with pediatric obsessive-compulsive disorder (p-OCD) (n = 457), along with concomitant specific features in the framework of different symptom dimensions/phenotypes, by a retrospective cross-sectional evaluation design. The most prevalent phenotype was obsession/checking (almost half), and the clinical features belonging to different phenotypes varied among sexes, age of onset, severity, and comorbidities. The contamination and aggressive obsessions, along with the compulsions such as cleaning and repeating routine activities, were the most prevalent symptoms, which were prevalently accompanied by generalized anxiety disorder, attention deficit hyperactivity disorder, and depression. Females with OCD were likely prone to exhibit comorbid internalizing disorders, whereas males were prone to externalizing. This recent study on a large Turkish clinical sample of p-OCD followed up within 5 years, highlighting separate evidence on subtyping of p-OCD in phenotype and comorbidity frame.


Endocrine differences in rams after genetic selection for testis size.
Testis diameter and body weight were recorded from 6 to 76 weeks of age in ram lambs from two established lines selected for high (H) and low (L) testis size. While testis growth was greater in the H line up to 14 weeks of age (P less than 0.001), body weight was significantly lower, with the L line rams being 10 kg heavier by 76 weeks. There were no differences in plasma LH up to 20 weeks of age, but FSH concentrations were significantly lower at 14 and 20 weeks in the H line. Testosterone concentrations were not significantly higher in the H line from 6 to 20 weeks. In lambs castrated at birth, significantly higher FSH values were recorded from 6 to 20 weeks of age in the H line (P less than 0.001) whereas there was no difference in LH concentration at 6 and 10 weeks of age between the lines. At 14 and 20 weeks, however, the concentrations of LH were greater in the H than L line lambs (P less than 0.05). After hemicastration at 6 weeks of age, the rate of growth of the remaining testis in the L line lambs was significantly faster than in entire lambs of that line from 10 to 20 weeks (P less than 0.05 at 10 weeks to P less than 0.001 at 20 weeks). There was no difference in the rate of testis growth between the the entire and hemicastrated lambs from the H line from 6 to 12 weeks of age. It can be concluded that there is an underlying genetic difference in pituitary gland and/or hypothalamic activity in ram lambs from the two selected lines.


Comparison of the milk-clotting properties of three plant extracts.
Several proteases from plant sources have been proposed as milk coagulants, however, limited research has been done on their milk-clotting properties. The effect of temperature on the milk-clotting activity of kiwi fruit, melon and ginger extracts was evaluated, as well as the effects of the different extracts on curd properties. Melon extracts showed high milk-clotting activity over a broad temperature range (45-75 °C) while kiwi fruit and ginger extracts showed high activity over a narrower temperature range, with a maximum at 40 and 63 °C, respectively. Curds produced using kiwi extracts had textural properties comparable with those obtained using commercial rennet, while melon extracts produced a fragile gel and low curd yield. The milk-clotting behavior of the three plant extracts was related to the protease specificity present in these extracts. The kiwi proteases displayed chymosin-like properties and thus hold the best potential for use as a milk coagulant in cheese production.


Associations between body mass and the outcome of surgery for scoliosis in Chinese adults.
In this study we intended to prove that being overweight has an unfavorable impact on the surgical treatment outcome of adult idiopathic scoliosis (AdIS). This is a retrospective study on the surgical treatment of seventy-one more than 30 years old (58 females and 13 males; mean age 42.9±12.2) idiopathic scoliotic patients with a minimum follow up of at least 2 years. The patients were divided into an overweight group (BMI≥23) and a non-overweight group (BMI<23). Preoperative, postoperative first erect and final follow-up radiographic measures, perioperative data, the Oswestry disability index (ODI), and the visual analog scale (VAS) were reviewed and compared. In the overweight group, no significant differences in radiographic measures, perioperative data, preoperative comorbidities, or postoperative complications, except for the more frequent concomitance of preoperative thoracic kyphosis 37.9±7.7 vs. 26.5±11.8 (P = 0.000) and thoracolumbar kyphosis 14.9±10.1 overweighted group vs. 6.5±9.9 non-overweighted group respectively (P = 0.002) were found. A higher morbidity of hypertension 36.8% vs. 9.6% (P = 0.004) was also observed in the overweight group. Postoperative ODI and VAS improved significantly in both groups compared to pre-operative values. The postoperative ODI of the overweight group (19.6±12.4) was significantly higher than that of the non-overweight group (12.4±7.9) (P = 0.022). Overweight adult idiopathic scoliotic patients had more frequent concomitance of preoperative thoracic kyphosis and thoracolumbar kyphosis and more serious postoperative pain. However, BMI did not affect the outcomes of surgical correction for coronal and sagittal scoliotic deformity and their postoperative complication rates were not significantly affected.


Highly active neutral ruthenium(II) arene complexes: synthesis, characterization, and investigation of their anticancer properties.
Reactions of ω-diphenylphosphino-functionalized alkyl phenyl sulfides Ph(2)P(CH(2))(n)SPh (n=1, L1; 2, L2; 3, L3), sulfoxides Ph(2)P(CH(2))(n)S(O)Ph (n=1, L4; 2, L5; 3, L6) and sulfones Ph(2)P(CH(2))(n)S(O)(2)Ph (n=1, L7; 2, L8; 3, L9) with the dinuclear chlorido bridged ruthenium(II) complex [{Ru(η(6)-p-cymene)Cl(2)}(2)] afforded mononuclear ruthenium(II) complexes of the type [Ru(η(6)-p-cymene)Cl(2){Ph(2)P(CH(2))(n)S(O)(x)Ph-κP}] (n/x=1/0, 1; 2/0, 2; 3/0, 3; 1/1, 4; 2/1, 5; 3/1, 6; 1/2, 7; 2/2, 8; 3/2, 9) having the P(∩)S(O)(x) ligands κP coordinated. The complexes were characterized by (1)H, (13)C and (31)P NMR spectroscopy. The crystal structures of complexes 2, 7·CH(2)Cl(2) and 8 were determined by X-ray diffraction analysis. All complexes have been screened for cytostatic activity against cell lines 518A2, 8505C, A253, MCF-7, and SW480. In vitro biological experiments demonstrate that these compounds are active toward the used cell lines. The ruthenium(II) complex [Ru(η(6)-p-cymene)Cl(2){Ph(2)P(CH(2))(2)SPh-κP}] (2) is the most active compound in the human cancer cell line MCF-7 with the IC(50) value 1.4 μM lower than cisplatin (2.0 μM).


Animal coloration research: why it matters.
While basic research on animal coloration is the theme of this special edition, here we highlight its applied significance for industry, innovation and society. Both the nanophotonic structures producing stunning optical effects and the colour perception mechanisms in animals are extremely diverse, having been honed over millions of years of evolution for many different purposes. Consequently, there is a wealth of opportunity for biomimetic and bioinspired applications of animal coloration research, spanning colour production, perception and function. Fundamental research on the production and perception of animal coloration is contributing to breakthroughs in the design of new materials (cosmetics, textiles, paints, optical coatings, security labels) and new technologies (cameras, sensors, optical devices, robots, biomedical implants). In addition, discoveries about the function of animal colour are influencing sport, fashion, the military and conservation. Understanding and applying knowledge of animal coloration is now a multidisciplinary exercise. Our goal here is to provide a catalyst for new ideas and collaborations between biologists studying animal coloration and researchers in other disciplines.This article is part of the themed issue 'Animal coloration: production, perception, function and application'.


Do technically efficient surgeons continue to provide active clinical services in a university hospital?
It is difficult for university hospitals to recruit and retain technically efficient surgeons because their missions include teaching and research as well as clinical services. The authors hypothesized that technically efficient surgeons do not continue to provide active clinical services in a university hospital. The authors collected data from all the surgical procedures performed at Teikyo University Hospital from April 1 through September 30 in 2013-2018. The dependent variable was defined as a length of each surgeon's active clinical services measured by month. Data envelopment analysis was employed to calculate each surgeon's technical efficiency score. Five control variables were selected; experience, medical school, surgical volume, gender, and academic ranks. Multiple regression analysis was performed. Efficiency scores had significantly negative association with length of active clinical services. Experience and surgical volume had significantly positive association with length of active clinical services. The other coefficients of control variables were insignificant. Technically efficient surgeons provide shorter active clinical services in a university hospital.


Phase resetting curves and oscillatory stability in interneurons of rat somatosensory cortex.
Synchronous oscillations in neural activity are found over wide areas of the cortex. Specific populations of interneurons are believed to play a significant role in generating these synchronized oscillations through mutual synaptic and gap-junctional interactions. Little is known, though, about the mechanism of how oscillations are maintained stably by particular types of interneurons and by their local networks. To obtain more insight into this, we measured membrane-potential responses to small current-pulse perturbations during regular firing, to construct phase resetting curves (PRCs) for three types of interneurons: nonpyramidal regular-spiking (NPRS), low-threshold spiking (LTS), and fast-spiking (FS) cells. Within each cell type, both monophasic and biphasic PRCs were observed, but the proportions and sensitivities to perturbation amplitude were clearly correlated to cell type. We then analyzed the experimentally measured PRCs to predict oscillation stability, or firing reliability, of cells for a complex stochastic input, as occurs in vivo. To do this, we used a method from random dynamical system theory to estimate Lyapunov exponents of the simplified phase model on the circle. The results indicated that LTS and NPRS cells have greater oscillatory stability (are more reliably entrained) in small noisy inputs than FS cells, which is consistent with their distinct types of threshold dynamics.


Diagnostic value of C- reactive protein and haematological parameters in neonatal sepsis.
To analyse various parameters of sepsis screen singly and in combination to formulate a guideline for the diagnosis of neonatal sepsis. A cross-sectional analytical study. The neonatal intensive care unit at the Paediatric Department, Military Hospital, Rawalpindi, over a period of seven months from 1st June to 31st December 2003. One hundred neonates having clinical features of sepsis and 100 normal asymptomatic neonates were evaluated with a set of investigations. C-reactive protein (CRP), erythrocyte sedimentation rate, total leukocyte count, absolute neutrophil count (ANC), immature neutrophils to total neutrophil count ratio (I/T ratio), thrombocytopenia, degenerative changes in the neutrophils and gastric aspirate cytology (GAC) for polymorphs were used for diagnosis of neonatal sepsis. CRP was positive in 24/28 (85.7%) of group-A (proven sepsis) and 58/72 (80.5%) of group-B (probable sepsis) and had a specificity of 95%. ANC was the second most sensitive test having sensitivity of 71.4 % for group-A and 63.9 % for group-B and 88% specificity. For group-A, sensitivity of GAC for polymorphs and platelet count was 71.4% and 64.3% respectively. The sensitivity, specificity and predictive values (PV) of the individual tests and different tests combination was also calculated for group-A and B. A set of investigations including CRP, TLC, ANC, thrombocytopenia, cytoplasmic vacuolization in the neutrophils and GAC for polymorphs are highly sensitive in detection of culture negative cases of neonatal sepsis. Moreover, a combination of three tests enhances the sensitivity of these tests.


The o-mannosylation pathway: glycosyltransferases and proteins implicated in congenital muscular dystrophy.
Several forms of congenital muscular dystrophy, referred to as dystroglycanopathies, result from defects in the protein O-mannosylation biosynthetic pathway. In this minireview, I discuss 12 proteins involved in the pathway and how they play a role in the building of glycan structures (most notably on the protein α-dystroglycan) that allow for binding to multiple proteins of the extracellular matrix.


Nonkitotoc hyperosmolar hyperglycemia during glycerol therapy for cerebral edema.
Glycerol, an effective cerebral dehydrating agent, also has gluconeogenic properties, and can thereby elevate serum glucose to dangerously high levels in predisposed patients treated for cerebral edema. The nonketotic hyperosmolar hyperglycemic state usually occurs in cases of maturity onset diabetes or prediabetes, as in the two elderly patients discussed in this paper. The pathogenesis usually evolves through a constant diabetogenic stress that causes persistent hyperglycemia resulting in the exhaustion of ordinarily adequate insulin stores, ultimately allowing hyperglycemia to progress unchecked to metabolic coma. Precautions to recognize this development should be taken in appropriate patients.


Factors affecting 2-hydroxypropiophenone formation by benzoylformate decarboxylase from Pseudomonas putida.
Benzoylformate (100 mM) was quantitatively converted to the acyloin compound, 2-hydroxypropiophenone (61.76 mM) and benzaldehyde (38.2 mM) by an enzyme extract from Pseudomonas putida ATCC 12633 in the presence of 1.6M acetaldehyde. Biotransformations were carried out at pH 6.0 and 30 degrees C with an incubation time of 60 min. Activity of the acyloin forming enzyme, benzoylformate decarboxylase, was 1.23 units/mL in the biotransformation mixture. Acyloin formation increased dramatically with pH in the range 4-5 and had a broad activity plateau in the pH range 5-8. A broad temperature optimum for acyloin formation was also observed in the range 20-40 degrees C.


Whitening dentifrice and tooth surface discoloration-a systematic review and meta-analysis.
The aim of this systematic review was to assess the effect of a whitening dentifrice (WDF) relative to a regular dentifrice (RDF) on the reduction of natural extrinsic tooth surface discoloration (ETD). The MEDLINE-PubMed, Cochrane-CENTRAL and EBSCO-Dentistry and Oral Sciences databases were searched, up to April 2017. The inclusion criteria were as follows:(randomized)controlled clinical trials, healthy subjects ≥18 years of age, studies comparing WDF with RDF, a follow-up period of at least 6 weeks and studies scoring ETD as the stain area/extent, stain intensity or a composite score. Studies using an induced staining model were excluded. Independent screening of 851 unique papers resulted in 21 eligible publications, which included 32 comparisons. The descriptive analysis illustrated that the majority of comparisons showed a significant effect on ETD, in favour of WDF over RDF. The meta-analysis substantiated this observation and revealed that the difference of means (diffM) comparing WDF and RDF was a reduction for stain area of -0.44 [(95% CI: -0.55; -0.339) (P<.00001)] according to the original Lobene Stain Index; this result is in favour of the WDF. For the modified Lobene Stain Index, the diffM was -0.41 [(95% CI: -0.71; -0.10) (P=.009)]. For overall stain intensity, the diffM was -0.35 [(95% CI: -0.44; -0.25) (P<.00001)], and the composite score was -0.39 [(95% CI: -0.57; -0.21) (P<.0001)] and -0.54 [(95% CI: -0.66; -0.43) (P<.00001)]. Subgroup analysis differentiating between products that contained added chemical antidiscoloration agents showed a similar pattern. In this review, nearly all dentifrices that are specifically formulated for tooth whitening were shown to have a beneficial effect in reducing ETD, irrespective of whether or not a chemical discoloration agent was added.


[Antiangiogenic therapy for gastrointestinal tumors].
Angiogenesis plays a major role in the pathogenesis of many disorders. Vascular endothelial growth factor has been shown to be the key regulator of normal and pathological angiogenesis. Increased expression of VEGF has been associated with tumor neovascularization, metastasis and proliferation of cancer cells. Bevacizumab, a monoclonal antibody against VEGF, has shown promising preclinical and clinical activity against different types of cancer, particularly in combination with chemotherapy. There is an increasing evidence that bevacizumab has a disease-modifying effect in metastatic colorectal carcinoma (CRC), and also in advanced hepatocellular carcinoma. Further investigation is needed to evaluate the role of antiangiogenic therapeutic strategies in other gastrointestinal malignancies. This review summarizes recent knowledge about antiangiogenic therapy for gastrointestinal cancers.


DPI-3290 [(+)-3-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. II. A mixed opioid agonist with potent antinociceptive activity and limited effects on respiratory function.
Allyl-2,5-dimethyl-1-piperazines have been of interest as analgesic agents for the management of moderate-to-severe pain. In this study, we compared the antinociceptive properties and respiratory depressant activity of one such agent, (+)-3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide (DPI-3290), with those of established narcotic analgesics, morphine and fentanyl. Intravenous administration of DPI-3290 in conscious laboratory rats increased antinociception in a dose-dependent manner with a corresponding ED(50) value of 0.05 +/- 0.0072 mg/kg. Simultaneous measurement of arterial blood gas in animals treated with DPI-3290 demonstrated dose-dependent increases in pCO2 with an ED(50) value of 0.91 +/- 0.22 mg/kg. In comparison, morphine and fentanyl increased antinociception in rats with ED(50) values of 2.01 +/- 0.0005 and 0.0034 +/- 0.00024 mg/kg, respectively, and the ED(50) value for morphine-induced changes in pCO2 was 4.23 +/- 0.72 mg/kg, whereas the ED(50) value for fentanyl-induced changes in pCO2 was 0.0127 +/- 0.0035 mg/kg. A separate series of experiments were designed to examine the effects of DPI-3290 on mu-opioid receptor induced antinociception and hypercapnia. Intravenous bolus doses of DPI-3290 that ranged from 0.2 to 1.0 mg/kg had no effect on antinociception mediated by alfentanil (2 microg/kg/min i.v.) but reduced hypercapnia by approximately 50%. Results from these studies demonstrate the equivalent antinociceptive efficacy of DPI-3290, morphine, and fentanyl but dramatic differences in the hypercapnia that antinociceptive doses of these drugs produce. When measured simultaneously, DPI-3290 had an 18.2-fold difference in the ratio comparing the ED(50) value for antinociception with the ED(50) value for changes in pCO2; this ratio was 2.1 for morphine and 3.7 for fentanyl. Furthermore, DPI-3290 reduced the alfentanil-mediated hypercapnia without any effect on antinociception. Together, the balanced opioid agonist activity of DPI-3290 may provide a means of powerful analgesia while mitigating the mu-opioid receptor-mediated hypercapnia.


Anti-Inflammatory Effects of Vitisinol A and Four Other Oligostilbenes from Ampelopsis brevipedunculata var. Hancei.
In this study, the cytotoxicities and anti-inflammatory activities of five resveratrol derivatives-vitisinol A, (+)-ε-viniferin, (+)-vitisin A, (-)-vitisin B, and (+)-hopeaphenol-isolated from Ampelopsis brevipedunculata var. hancei were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lipopolysaccharide (LPS)-stimulated RAW264.7 cells, respectively. The result from MTT assay analysis indicated that vitisinol A has lower cytotoxicity than the other four well-known oligostilbenes. In the presence of vitisinol A (5 μM), the significant reduction of inflammation product (nitric oxide, NO) in LPS-induced RAW264.7 cells was measured using Griess reaction assay. In addition, the under-expressed inflammation factors cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in LPS-induced RAW264.7 cells monitored by Western blotting simultaneously suggested that vitisinol A has higher anti-inflammatory effect compared with other resveratrol derivatives. Finally, the anti-inflammatory effect of vitisinol A was further demonstrated on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear edema in mice. As a preliminary functional evaluation of natural product, the anti-inflammatory effect of vitisinol A is the first to be examined and reported by this study.


Single-electron entrapment of [8]annulyne, biannulenylenes, and an annulenoannulene.
The low-temperature (-100 degrees C) dehydrohalogenation of bromocyclooctatetraene followed by immediate electron-transfer yields a stable solution of the [8]annulyne anion radical. If the unstable [8]annulyne is reacted with itself, cyclobutadiene, or benzyne, the respective bi-[8]annulenylene, [6]annuleno[8]annulene, or [6]-[8]annulenylene can be trapped as their anion radicals via one-electron transfer. These condensation products were all obtained from simple [2 + 2] cycloaddition reactions. B3LYP/6-31G geometry optimizations were carried out, and the calculated spin densities were compared to the EPR spectral results obtained for the anion radicals of [6]annuleno[8]annulene, [8]annulyne, bi[8]annulenylene, and [6]-[8]annulenylene, and excellent agreement has been realized. This simple "one-pot" approach should be applicable to a wide range of such systems.


Cardiovascular changes in dogs given diazepam and diazepam-ketamine.
The cardiopulmonary consequences of diazepam (0.5 mg/kg, IV) followed by ketamine (10 mg/kg, IV) were evaluated in 11 dogs. Diazepam did not exhibit a tranquilizing effect and was frequently associated with excessive excitement. It produced minimal cardiopulmonary effects, except for a significant increase in heart rate. Ketamine administration was associated with less cardiovascular stimulation when administered after diazepam than it did when administered alone; the respiratory depression was greater. Compared with ketamine alone, the diazepam-ketamine combination was associated with more vomition, less muscle hypertonus, less seizure activity, and less salivation.


Myocarditis with concomitant tuberculosis infection presenting with solitary ventricular tachycardia: a case report.
Myocarditis is an infrequent extrapulmonary manifestation of tuberculosis that confers an unfavourable prognosis. A 36-year-old man presented to the hospital with palpitations and dyspnoea. Tests revealed the presence of non-sustained ventricular tachycardia, with mild elevation of troponin and C-reactive protein levels. Coronary angiography showed normal results. A cardiac magnetic resonance (CMR) showed moderate hypertrophy, preserved ejection fraction, and an extensive multi-segmental pattern of fibrosis and oedema. An 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET-CT) scan revealed multiple hypermetabolic adenopathies and patchy cardiac uptake. A tuberculin skin test and interferon-gamma release assay were both positive. An endomyocardial biopsy (EMB) showed inflammation without granulomas; and microbiological stains were negative. Biopsy of an adenopathy revealed the presence of multiple necrotizing granulomas with Langhans cells. Based on the test results and clinical presentation, the suspected diagnosis was tuberculous myocarditis. Treatment with anti-tuberculosis drugs was started. One month later, the presence of mycobacterium tuberculosis (MT) was detected in the lymph node culture. At 7 months of follow-up, the patient remains asymptomatic, ventricular arrhythmias have ceased, and radiological signs of inflammation have resolved. Ventricular arrhythmia is one of the clinical manifestations of tuberculous myocarditis. Cardiac magnetic resonance and 18F-FDG-PET-CT imaging are an essential component of the non-invasive evaluation of inflammatory cardiomyopathy. However, a confirmatory biopsy may be required to identify potentially treatable aetiologies. Although the diagnosis of tuberculous myocarditis requires an isolation of MT by staining or culture in EMB, the diagnostic yield is very low. For this reason, extra-cardiac findings may provide the definitive diagnostic clue.


Cloning of gene responsible for tributyltin chloride (TBTC1) resistance in TBTC1-resistant marine bacterium, Alteromonas sp. M-1.
A genetic library of tributyltin chloride (TBTC1)-resistant marine bacterium, Alteromonas sp. M-1, was constructed using plasmid vector pUC 19. Three positive clones were obtained from E. coli JM 109 transformed with the plasmids by the method of replica plating to LB medium containing 1 mM TBTC1. These clones could grow in LB liquid medium containing 100 microM TBTC1. Plasmids harbouring genes of Alteromonas sp. M-1 were designated pTBT1, pTBT2 and pTBT3 which contain 1.8 kb Hind III-fragment, 4.8 kb Pst I-fragment and 7.8 kb Pst I-fragment, respectively. Nucleotide sequence of the shortest fragment, 1.8 kb Hind III-fragment was determined, revealing an open reading frame (ORF) was contained in the fragment. The ORF was 324 bp (108 amino acids). The 48.5% of the amino acids encoded was hydrophobic, suggesting that the product relating to TBTC1 resistance might be membrane related protein. Homology search in amino acids alignment indicated that the product has homology with transport proteins.


Incidence of reciprocal synapses on outer hair cells of the human organ of Corti.
The incidence of reciprocal synapses at the base of outer hair cells of the human organ of Corti was studied by electron-microscopic serial section reconstruction. Reciprocal synapses were found in each of six ears from five individuals. A total of 1,386 serial sections and the neural poles of 25 outer hair cells in two individuals were examined. Fourteen of the 25 outer hair cells (56%) possessed reciprocal synapses. The incidence of reciprocal synapses increased from the first to the third rows of outer hair cells, as determined by the percentage of outer hair cells and afferent nerve terminals of each row demonstrating reciprocal synapses and the average number of reciprocal synapses per hair cell in each row. Hair cells with reciprocal synapses had more afferent and fewer efferent terminals per hair cell than hair cells without reciprocal synapses.


Valve surgery combined with myocardial revascularisation. Report of 62 cases.
Combined valvular and coronary bypass surgery was performed in 1984-1988 in 62 patients. Their age range at operation was 38-75 (mean 59) years and more than 90% were in NYHA class III or IV. Valve replacement was performed in 55 cases--mitral in 13, aortic in 33, tricuspid in one and combined valve procedures in eight cases--and valvular correction in seven cases. The patients also received a total of 92 coronary artery grafts (1-4/patient, mostly as single grafts). The hospital mortality was 3% and there were two late deaths. Follow-up was 100% complete 2-52 (mean 22) months after surgery, and more than 90% of the survivors were improved.