Sirolimus: a potent new immunosuppressant for liver transplantation.
Sirolimus (rapamycin) is a new immunosuppressant that appears to be synergistic with cyclosporine in kidney transplantation, but with a different side-effect profile. This pilot study evaluated sirolimus in liver transplantation. Patients undergoing orthotopic liver transplantation for primary tumors (8), and later for nonmalignant disease (7), received one of three sirolimus-based immunosuppressive regimens. Protocol A comprised sirolimus, microemulsion cyclosporine (target whole blood concentration: 100 ng/ml), and prednisolone; protocol B omitted prednisolone; and protocol C was sirolimus alone. By 3 months after transplantation, all patients were receiving sirolimus as monotherapy. Fifteen patients were treated with a follow-up of 117-806 days. Rejection was more common on monotherapy than double therapy, and absent on triple therapy. The drug was generally well tolerated, with only three patients discontinuing sirolimus: one for hyperlipidemia, one for pneumocystis pneumonia, and one for inability to tolerate the taste of the drug. Two patients discontinued cyclosporine early, both as a result of neurological complications; they continued on sirolimus monotherapy. Five patients died; one suffered a cardiac arrest, and four died from sepsis in association with graft-versus-host disease, recurrent tumor, a paralyzed right hemidiaphragm, and primary nonfunction. Sirolimus combined with cyclosporine provided potent immunosuppression of liver allografts, and sirolimus monotherapy was adequate and well tolerated as maintenance therapy. Side effects of sirolimus over the short period of follow-up were uncommon and reversible with dose reduction or cessation of therapy.


Utilization of nursing research in practice and application strategies to raise research awareness amongst nurse practitioners: a model for success.
This paper describes the views of nurse practitioners regarding the utilization of nursing research in practice and puts forward four major strategies to raise research awareness amongst students and qualified nursing staff. The aims of the study were to describe the extent to which nursing research was being used in practice and secondly the degree of nurses' awareness of current research findings relevant to their daily work. Attention also focused on strategies needed to improve research awareness amongst nurse practitioners. The study was centred on two large district general hospitals, chosen to provide contrasts. Data were collected at two points in time, over a 2 1/2-year period, using in-depth individual and group interviews. The results of the study showed that research awareness amongst many nurses and research utilization in several practice areas were poor despite availability of a number of relevant and well-established nursing research findings. It also showed that resistance to applying nursing research to practice was often high, particularly amongst more senior nursing staff. However, it could be changed if researchers, nursing lecturers and nurse practitioners work jointly together towards promoting nursing research in practice and using: facilitation, support and encouragement; role modelling; consistency; and application in clinical practice.


Molecular Orientation in a Variable-Focus Liquid Crystal Lens Induced by Ultrasound Vibration.
A method to estimate orientation direction of liquid crystal molecules three-dimensionally under ultrasound excitation was proposed and the relationship between the ultrasound vibration and the molecular orientation was discussed. Our group have reported a technique to control orientation direction of liquid crystal molecules using ultrasound vibration which could be applied to an optical variable-focus liquid crystal lens. The lens consisted of a liquid crystal layer sandwiched by two glass circular discs and a piezoelectric ring. Ultrasound vibration induces change in the refractive index of the lens, enabling the variable-focus function. The three-dimensional orientation direction of the liquid crystal molecules in the lens was predicted from the transmitted light distributions under the crossed Nicol conditions. The liquid crystal molecules were inclined from vertical alignment by the ultrasound vibration, and larger ultrasound vibration gave larger inclination of the molecules. There was a strong correlation between the distributions of ultrasound vibration and the liquid crystal molecular orientation; the molecular orientation was changed remarkably between the antinodal and nodal parts of the ultrasound flexural vibration on the glass plate and the molecules aligned towards the antinode.


Varying the hydrophobicity of humic matter by a phase-transfer-catalyzed O-alkylation reaction.
An O-alkylation reaction catalyzed by tetrabutylammonium hydroxide (TBAH) as a phase-transfer agent was applied to a humic acid (HA) to modify its hydrophobic properties. The carboxyl and hydroxyl functional groups of HA acted as nucleophiles in substitution reactions (Sn2) with methyl iodide, pentyl bromide and benzyl bromide added in amounts equimolar to 20, 60 and 80% of HA total nucleophilic sites. The occurrence of O-alkylation was shown by DRIFT spectrometry, NMR spectroscopy, High Performance Size Exclusion Chromatography (HPSEC) and elemental analysis of reaction products. DRIFT spectra showed changes in C-H stretching and bending regions following the insertion of methyl and pentyl groups, while the incorporation of benzyl groups revealed the characteristics aromatic C-H stretching bands. Both liquid- and solid-state NMR spectra revealed characteristic signals for alkyl/aryl esters and ethers. HPSEC chromatograms of alkylated materials invariably displayed an increase in hydrodynamic volume in respect to the original HA, thereby suggesting that the enhanced hydrophobicity conveyed further associations among humic molecules. Analytical, HPSEC and spectroscopic results suggest that benzylation was the most effective reaction at all percentages of HA total nucleophilicity, followed, in the order, by pentylation and methylation, The benzylation reaction was used to improve reaction and work-up conditions and show that HA could be efficiently alkylated also with substantial reduction of TBAH amount, with no THF addition, increase of reaction time and of washing cycles to remove catalyst impurities. These findings indicate that the hydrophobicity of humic substances can be modulated through a mild O-alkylation reaction under a phase-transfer catalysis according to the extent of exposed HA nucleophilic sites. Such a structural modification of humic matter may have multiple chemical, environmental and biological applications.


Response diversity can increase ecological resilience to disturbance in coral reefs.
Community-level resilience depends on the interaction between multiple populations that vary in individual responses to disturbance. For example, in tropical reefs, some corals can survive higher stress (resistance) while others exhibit faster recovery (engineering resilience) following disturbances such as thermal stress. While each type will negatively affect the other through competition, each might also benefit the other by reducing the potential for an additional competitor such as macroalgae to invade after a disturbance. To determine how community composition affects ecological resilience, we modeled coral-macroalgae interactions given either a resistant coral, a resilient coral, or both together. Having both coral types (i.e., response diversity) can lead to observable enhanced ecological resilience if (1) the resilient coral is not a superior competitor and (2) disturbance levels are high enough such that the resilient coral would collapse when considered alone. This enhanced resilience occurs through competitor-enabled rescue where each coral increases the potential for the other to recover from disturbance through external recruitment, such that both corals benefit from the presence of each other in terms of total cover and resilience. Therefore, conservation management aimed at protecting resilience under global change requires consideration of both diversity and connectivity between sites experiencing differential disturbance.


Serial surveillance cultures of skin and catheter hub specimens from critically ill patients with central venous catheters: molecular epidemiology of infection and implications for clinical management and research.
A prospective study of 45 central venous catheters was conducted to assess, by strain delineation, the turnover of skin and catheter hub (superficial) colonization and the relative contributions of catheter hub and skin colonization to catheter tip colonization. Serial quantitative cultures of skin and catheter hub were performed. Catheter tip, blood, and specimens for culture from targeted superficial sites (TSSs) were also collected at the time of catheter removal. Strains from 17 tip-positive catheters were delineated by pulsed-field gel electrophoresis. Only 12 (28.6%) of 42 skin strains and 14 (31.1%) of 45 catheter hub strains were found to be present at the time of catheter removal. In addition, only 9 (29.0%) of the 31 tip-colonizing strains were present on TSSs. Moreover, 15 (48.4%) of the 31 tip-colonizing strains had a superficial origin, and the other 16 (51.6%) were of unknown origin. In catheters suspected of infection, cultures of TSSs had a negative predictive value for catheter-related bacteremia of 94.4% but a positive predictive value of 44.4%. When the causative agent was identified (to the strain level) these values dropped to 80.9 and 18.7%, respectively. The study shows that skin and catheter hub colonization is a common, dynamic phenomenon. Strains recovered from TSSs showed a low level of correlation with strains from previous cultures of specimens from superficial sites and catheter tip isolates. Consequently, TSSs cannot be recommended for use in determining the therapy. However, catheter-related bacteremia is uncommon when cultures of TSSs are negative.


Response to HAART and GB virus type C coinfection in a cohort of antiretroviral-naive HIV-infected individuals.
The prognostic role of GB virus type C (GBV-C) viraemia in HIV-infected subjects treated with highly active antiretroviral therapy (HAART) is still undefined. The aim of this analysis is to assess the relationship between GBV-C infection and response to antiretroviral therapy among HIV-infected subjects initiating HAART when antiretroviral-naive. A prospective, observational study of 400 HIV-infected patients with measurements of GBV-C RNA, hepatitis C virus (HCV) antibodies and HCV RNA determined from plasma stored prior to HAART initiation. Time to virological (achieving HIV RNA < or =500 copies/ml) and immunological success (a CD4+ count increase of > or =200 cells/microl), and the time to virological relapse (confirmed HIV RNA >500 copies/ml) were assessed by Kaplan-Meier methods and Cox proportional hazard regression model. Of the subjects, 117 (29.3%) were GBV-C positive and, overall, 351 (87.8%) patients achieved virological success. After controlling for a number of confounders including HCV RNA, GBV-C viraemic patients experienced a significantly lower risk of HIV rebound than those who were GBV-C negative [relative hazard (RH)=0.56, 95% CI: 0.34-0.93, P=0.03]. Conversely, the probability of achieving initial virological success or CD4+ count response after HAART did not differ between GBV-C-negative and -positive subjects. These results suggest that GBV-C coinfection may play a role in determining the rate of HIV rebound possibly by competing with HIV replication after HIV load has been successfully suppressed by HAART.


BDNF-dependent stimulation of dopamine D5 receptor expression in developing striatal astrocytes involves PI3-kinase signaling.
It is well known that brain-derived neurotrophic factor (BDNF) and the early nigrostriatal dopaminergic input are implicated in the regulation of developmental processes in the neostriatum. There is growing evidence that interactions between these developmental signals rather than singular actions are critical for cellular differentiation and compartmentation of the striatum. In the present report, our goal is to identify striatal target cells for BDNF and dopamine. Using primary neuronal and astroglial cell cultures, we have demonstrated that BDNF selectively regulates D(5) but not D(1) receptor expression in astrocytes. This effect was not observed in neurons. Pharmacological approaches indicated that BDNF effects on dopamine D(5) receptor expression were mediated at the intracellular level by an activation of the PI3- but not MAP-kinase cascade. FACS analysis and confocal laser microscopy revealed that the newly synthesized D(5) receptors were integrated into the plasma membrane of astrocytes. Our findings clearly show that developing striatal astrocytes are targets for BDNF. Furthermore, BDNF appears to regulate the dopamine responsiveness of astrocytes. This implicates that functional interactions between BDNF, dopamine, and astrocytes are necessary to warrant proper differentiation of the striatal anlage.


[MRI-guided pediatric interventions].
There are only a few diagnostic or therapeutic procedures where MR imaging is applied during pediatric interventions. This study will describe indications, complications as well as the advantages and disadvantages of MRI-guided interventions based on a case study in an open MRI scanner. 14 procedures were performed in an open MRI scanner (Signa SP/i, GEMS) on 13 children (1 - 16 yr) with bone, soft tissue and brain lesions (1 - 4 cm diameter). Localization of the pathology, targeting and final control of the result were based on images acquired with SE-, 3D-, GE-sequences pre- and post-contrast as well as FSE-sequences. Interactive MRI-guided instrument navigation was performed using a multiplanar T1w GE-sequence. Eight biopsies (incl. 1 rebiopsy), two tumor resections, one removal of a free joint mouse and three tumor-markings were performed without complications. Five biopsies provided appropriate sample quality for a histological diagnosis while two samples were too fragmented requiring a second biopsy (one of them MRI-guided). Surgical progress during tumor resection and marking could be controlled during the intervention without repositioning the patient. MR image guided pediatric interventions combine the advantage of an imaging system without ionizing radiation and the high soft-tissue contrast. The low number of these kinds of procedures can be explained by the relatively high costs for the intervention, the increased duration for each procedure and the limited availability of open MRI systems. The integrated localization-system helps during planning of the access path when facing complex anatomical structures and provides safe navigation in sensitive regions like the epiphyseal cartilage. Recent and expected developments of the required MR-compatible biopsy instruments could provide higher efficiency for appropriate sample size and quality. Summarizing, MRI-guided pediatric interventions have shown to be a promising method at the beginning of its development.


A comparison of patients' and pharmacists' satisfaction with medication counseling provided by community pharmacies: a cross-sectional survey.
Medication counseling is a critical component of pharmaceutical care to promote the safe and effective use of medications and to maximize therapeutic outcomes. The assessment of patients' and pharmacists' satisfaction with medication counseling services could be one of the vital parameters for predicting the quality of pharmacy services. No study has measured and compared both patients' and pharmacists' satisfaction with medication counseling. The objectives of this study were to describe and compare patients' and pharmacists' levels of satisfaction with medication counseling services offered by community pharmacists in South Korea. This was a descriptive, cross-sectional survey. The online survey was distributed to patients and community pharmacists using a structured questionnaire. The questionnaires consisted of 4 main areas: (1) responders' characteristics (2) current state of medication counseling methods provided by community pharmacies (3) overall satisfaction with medication counseling (4) demand for the development of medication counseling standards. A comparison between patients and pharmacists was made using either a chi-square test or a Fisher's exact test. Between June 13, 2014 and July 15, 2014, a total of 252 patients and 620 pharmacists completed the survey. It was found that 47.3% of pharmacists and 34.0% of patients were satisfied with the current medication counseling service. Pharmacists showed a higher degree of satisfaction with the medication counseling service compared to patients (p <0.05). A major reason for patients not being satisfied with the medication counseling from community pharmacists was the insufficient time spent on counseling (51.2%). The pharmacists' perception of a major barrier to providing appropriate medication counseling for patients was the lack of time (24.3%). Moreover, a substantial number of patients (88%) and pharmacists (73%) supported the development of medication counseling standards to improve community pharmacist counseling services (p < 0.001). This study showed that both patients and pharmacists have low levels of satisfaction with the current medication counseling service offered by community pharmacists. This study provides baseline data for the development of national guidelines for medication counseling by pharmacists.


Lane detection by orientation and length discrimination.
This paper describes a novel lane detection algorithm for visual traffic surveillance applications under the auspice of intelligent transportation systems. Traditional lane detection methods for vehicle navigation typically use spatial masks to isolate instantaneous lane information from on-vehicle camera images. When surveillance is concerned, complete lane and multiple lane information is essential for tracking vehicles and monitoring lane change frequency from overhead cameras, where traditional methods become inadequate. The algorithm presented in this paper extracts complete multiple lane information by utilizing prominent orientation and length features of lane markings and curb structures to discriminate against other minor features. Essentially, edges are first extracted from the background of a traffic sequence, then thinned and approximated by straight lines. From the resulting set of straight lines, orientation and length discriminations are carried out three-dimensionally with the aid of two-dimensional (2-D) to three-dimensional (3-D) coordinate transformation and K-means clustering. By doing so, edges with strong orientation and length affinity are retained and clustered, while short and isolated edges are eliminated. Overall, the merits of this algorithm are as follows. First, it works well under practical visual surveillance conditions. Second, using K-means for clustering offers a robust approach. Third, the algorithm is efficient as it only requires one image frame to determine the road center lines. Fourth, it computes multiple lane information simultaneously. Fifth, the center lines determined are accurate enough for the intended application.


A Parallel Multiclassification Algorithm for Big Data Using an Extreme Learning Machine.
As data sets become larger and more complicated, an extreme learning machine (ELM) that runs in a traditional serial environment cannot realize its ability to be fast and effective. Although a parallel ELM (PELM) based on MapReduce to process large-scale data shows more efficient learning speed than identical ELM algorithms in a serial environment, some operations, such as intermediate results stored on disks and multiple copies for each task, are indispensable, and these operations create a large amount of extra overhead and degrade the learning speed and efficiency of the PELMs. In this paper, an efficient ELM based on the Spark framework (SELM), which includes three parallel subalgorithms, is proposed for big data classification. By partitioning the corresponding data sets reasonably, the hidden layer output matrix calculation algorithm, matrix decomposition algorithm, and matrix decomposition algorithm perform most of the computations locally. At the same time, they retain the intermediate results in distributed memory and cache the diagonal matrix as broadcast variables instead of several copies for each task to reduce a large amount of the costs, and these actions strengthen the learning ability of the SELM. Finally, we implement our SELM algorithm to classify large data sets. Extensive experiments have been conducted to validate the effectiveness of the proposed algorithms. As shown, our SELM achieves an speedup on a cluster with ten nodes, and reaches a speedup with 15 nodes, an speedup with 20 nodes, a speedup with 25 nodes, a speedup with 30 nodes, and a speedup with 35 nodes.


Imaging expression of cytosine deaminase-herpes virus thymidine kinase fusion gene (CD/TK) expression with [124I]FIAU and PET.
Double prodrug activation gene therapy using the Escherichia coli cytosine deaminase (CD)-herpes simplex virus type 1 thymidine kinase (HSV1-tk) fusion gene (CD/TK) with 5-fluorocytosine (5FC), ganciclovir (GCV), and radiotherapy is currently under evaluation for treatment of different tumors. We assessed the efficacy of noninvasive imaging with [124I]FIAU (2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyl-5-iodo-uracil) and positron emission tomography (PET) for monitoring expression of the CD/TK fusion gene. Walker-256 tumor cells were transduced with a retroviral vector bearing the CD/TK gene (W256CD/TK cells). The activity of HSV1-TK and CD subunits of the CD/TK gene product was assessed in different single cell-derived clones of W256CD/TK cells using the FIAU radiotracer accumulation assay in cells and a CD enzyme assay in cell homogenates, respectively. A linear relationship was observed between the levels of CD and HSV1-tk subunit expression in corresponding clones in vitro over a wide range of CD/TK expression levels. Several clones of W256CD/TK cells with significantly different levels of CD/TK expression were selected and used to produce multiple subcutaneous tumors in rats. PET imaging of HSV1-TK subunit activity with [124I]FIAU was performed on these animals and demonstrated that different levels of CD/TK expression in subcutaneous W256CD/TK tumors can be imaged quantitatively. CD expression in subcutaneous tumor sample homogenates was measured using a CD enzyme assay. A comparison of CD and HSV1-TK subunit enzymatic activity of the CD/TK fusion protein in vivo showed a significant correlation. Knowing this relationship, the parametric images of CD subunit activity were generated. Imaging with [124I]FIAU and PET could provide pre- and posttreatment assessments of CD/TK-based double prodrug activation in clinical gene therapy trials.


Effects of a saddle shaped annulus on mitral valve function and chordal force distribution: an in vitro study.
Studies have concluded that the shape of the human mitral valve annulus is a three-dimensional saddle. The objective of this study was to investigate the effects of a saddle shaped annulus on chordal force distribution and mitral valve function. Eleven human mitral valves were studied in a physiological left heart simulator with a variable shaped annulus (flat versus saddle). Cardiac output and transmitral pressure were analyzed to determine mitral regurgitation volume. In six experiments, force transducers were placed on six chordae tendineae to measure chordal force distribution. Valves were tested in normal and pathophysiologic papillary muscle positions. When comparing the flat and saddle shaped configurations, there was no significant difference in mitral regurgitation volume 11.2% +/- 24.7% (p = 0.17). In the saddle shaped configuration, the tension on the anterior strut chord was reduced 18.5% +/- 16.1% (p < 0.02), the tension on the posterior intermediate chord increased 22.3% +/- 17.1% (p < 0.03), and the tension of the commissural chord increased 59.0% +/- 32.2% (p < 0.01). Annular shape also altered the tensions on the remaining chords. Annular shape alone does not significantly affect mitral regurgitation caused by papillary muscle displacement. A saddle shaped annulus redistributes the forces on the chords by altering coaptation geometry, leading to an optimally balanced anatomic/physiologic configuration.


Perceived reciprocal value of health professionals' participation in global child health-related work.
Leading children's hospitals in high-income settings have become heavily engaged in international child health research and educational activities. These programs aim to provide benefit to the institutions, children and families in the overseas locations where they are implemented. Few studies have measured the actual reciprocal value of this work for the home institutions and for individual staff who participate in these overseas activities. Our objective was to estimate the perceived reciprocal value of health professionals' participation in global child health-related work. Benefits were measured in the form of skills, knowledge and attitude strengthening as estimated by an adapted Global Health Competency Model. A survey questionnaire was developed following a comprehensive review of literature and key competency models. It was distributed to all health professionals at the Hospital for Sick Children with prior international work experience (n = 478). One hundred fifty six health professionals completed the survey (34%). A score of 0 represented negligible value gained and a score of 100 indicated significant capacity improvement. The mean respondent improvement score was 57 (95% CI 53-62) suggesting improved overall competency resulting from their international experiences. Mean scores were >50% in 8 of 10 domains. Overall scores suggest that international work brought value to the hospital and over half responded that their international experience would influence their decision to stay on at the hospital. The findings offer tangible examples of how global child health work conducted outside of one's home institution impacts staff and health systems locally.


A termite symbiotic mushroom maximizing sexual activity at growing tips of vegetative hyphae.
Termitomyces mushrooms are mutualistically associated with fungus-growing termites, which are widely considered to cultivate a monogenotypic Termitomyces symbiont within a colony. Termitomyces cultures isolated directly from termite colonies are heterokaryotic, likely through mating between compatible homokaryons. After pairing homokaryons carrying different haplotypes at marker gene loci MIP and RCB from a Termitomyces fruiting body associated with Odontotermes formosanus, we observed nuclear fusion and division, which greatly resembled meiosis, during each hyphal cell division and conidial formation in the resulting heterokaryons. Surprisingly, nuclei in homokaryons also behaved similarly. To confirm if meiotic-like recombination occurred within mycelia, we constructed whole-genome sequencing libraries from mycelia of two homokaryons and a heterokaryon resulting from mating of the two homokaryons. Obtained reads were aligned to the reference genome of Termitomyces sp. J132 for haplotype reconstruction. After removal of the recombinant haplotypes shared between the heterokaryon and either homokaryons, we inferred that 5.04% of the haplotypes from the heterokaryon were the recombinants resulting from homologous recombination distributed genome-wide. With RNA transcripts of four meiosis-specific genes, including SPO11, DMC1, MSH4, and MLH1, detected from a mycelial sample by real-time quantitative PCR, the nuclear behavior in mycelia was reconfirmed meiotic-like. Unlike other basidiomycetes where sex is largely restricted to basidia, Termitomyces maximizes sexuality at somatic stage, resulting in an ever-changing genotype composed of a myriad of coexisting heterogeneous nuclei in a heterokaryon. Somatic meiotic-like recombination may endow Termitomyces with agility to cope with termite consumption by maximized genetic variability.


Accuracy and Utility of Frameless Stereotactic Placement of Stereoelectroencephalography Electrodes.
Successful surgery for epilepsy hinges on identification of the epileptogenic focus. Stereoelectroencephalography (sEEG) is the most effective way to identify most seizure foci. There are multiple methods of inserting depth electrodes, including frame-based, frameless, and robot-assisted techniques. Studies have shown the accuracy of frame-based and robotic-assisted techniques to be statistically similar, while only one study has detailed the frameless sEEG insertion technique. Patients underwent placement of sEEG depth electrodes using frameless stereotaxy from September 2019 to September 2021 at Geisinger Medical Center by a single surgeon. Seizure history, electrode placement accuracy relative to the planned trajectories, surgical times, success rate of identifying the epileptogenic focus, and subsequent seizure control rates after surgical treatment were documented. Data were available for 21 patients and 181 electrodes inserted using the VarioGuide frameless stereotactic system. Each insertion took an average of 14.5 minutes per lead. Average entry variance was 2.7 mm with an average target variance of 4.6 mm. The epileptogenic focus was identified in 19 of 21 patients, and further surgical treatment was performed in 18 of 21 patients (85.7%). VarioGuide frameless stereotaxy for sEEG placement is comparable to frame-based and robotic-assisted techniques with statistically similar rates of epileptic focus identification. Lead placement accuracy is slightly lower and time per lead is slightly higher relative to robot-assisted surgeries. When a robot system is unavailable, surgeons can consider using a frameless stereotactic technique for sEEG insertion, allowing patients to benefit from a similarly high rate of epileptic zone identification.


Increased excitability of aged rabbit CA1 neurons after trace eyeblink conditioning.
Cellular properties of CA1 neurons were studied in hippocampal slices 24 hr after acquisition of trace eyeblink conditioning in young adult and aging rabbits. Aging rabbits required significantly more trials than young rabbits to reach a behavioral criterion of 60% conditioned responses in an 80 trial session. Intracellular recordings revealed that CA1 neurons from aging control rabbits had significantly larger, longer lasting postburst afterhyperpolarizations (AHPs) and greater spike frequency adaptation (accommodation) relative to those from young adult control rabbits. After learning, both young and aging CA1 neurons exhibited increased postsynaptic excitability compared with their respective age-matched control rabbits (naive and rabbits that failed to learn). Thus, after learning, CA1 neurons from both age groups had reduced postburst AHPs and reduced accommodation. No learning-related differences were seen in resting membrane potential, membrane time constant, neuron input resistance, or action potential characteristics. Furthermore, comparisons between CA1 neurons from trace-conditioned aging and trace-conditioned young adult rabbits revealed no statistically significant differences in postburst AHPs or accommodation, indicating that similar levels of postsynaptic excitability were attained during successful acquisition of trace eyeblink conditioning, regardless of rabbit age. These data represent the first in vitro demonstration of learning-related excitability changes in aging rabbit CA1 neurons and provide additional evidence for involvement of changes in postsynaptic excitability of CA1 neurons in both aging and learning.


High-dispersion astronomical spectroscopy with holographic and ruled diffraction gratings.
Holographic gratings cause much less stray light and spectral degradation than classically ruled gratings. Their high groove densities enable high dispersion in first diffraction order and a high spectrograph through-put comparable to the best echelles. Their lower reflective efficiency is compensated by the avoidance of cross dispersers, enabling efficient high-fidelity spectroscopy with single-pass spectrographs. Instrumental profiles of the ESO coudé spectrograph with large holographic and ruled gratings have been studied in detail, and their effects on astronomical spectra are discussed and compared to those of other instruments.


Luteolytic effect of LH: inhibition of 3 beta-hydroxysteroid dehydrogenase and stimulation of 20 alpha-hydroxysteroid dehydrogenase luteal activities in late pregnant rats.
The mechanisms associated with the onset of luteolysis in the pregnant rat are not well known. The effect of a specific rat LH antiserum (AS-rLH) and of ovine LH (oLH) on luteal steroidogenesis on day 19 of pregnancy was examined. Rat LH antiserum administered intrabursally at 1000-1100 h on day 19 of pregnancy prevented the physiological decrease in 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity, the increase in 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSD) activity and the fall in serum progesterone (P4) level observed at 1800 h on day 21 of pregnancy. To see if oLH has a direct effect on luteal steroidogenesis, the gonadotrophin was injected into the periovarian bursa. The intrabursa treatment with 1 microgram oLH on day 19 of pregnancy at 0800-0900 h did not modify corpus luteal function 36 h after treatment, but treatment with 4 micrograms oLH per ovary induced a significant progressive decrease in luteal 3 beta-HSD activity starting 12 h after treatment, while a significant increase in 20 alpha-HSD activity, concomitant with a decrease in serum P4 level, occurred 48 h after treatment. Luteal P4 content decreased with respect to control groups 36 and 48 h after intrabursal treatment with 4 micrograms oLH. The intrabursal administration of 8 micrograms oLH induced an increase in 20 alpha-HSD activity and a decrease in 3 beta-HSD activity 36 h after treatment. Administration of 4 micrograms oLH per ovary on day 8 of pregnancy induced a significant increase in serum P4 levels without modifying 3 beta-HSD activity. In rats treated with oLH on day 19 of pregnancy the decrease in 3 beta-HSD activity occurred 36 h before the significant increase in 20 alpha-HSD activity and serum P4 level. In conclusion, the luteal enzymatic activity changes and the significant decrease in the intraluteal P4 concentration induced by the intrabursal administration of oLH and the clear effect of AS-rLH preventing the physiological luteal changes preceding parturition provide good evidence of an intraovarian action of LH during the normal progression of luteolysis in late pregnant rats.


Autoimmunity conferred by chs3-2D relies on CSA1, its adjacent TNL-encoding neighbour.
Plant innate immunity depends on the function of a large number of intracellular immune receptor proteins, the majority of which are structurally similar to mammalian nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) proteins. CHILLING SENSITIVE 3 (CHS3) encodes an atypical Toll/Interleukin 1 Receptor (TIR)-type NLR protein with an additional Lin-11, Isl-1 and Mec-3 (LIM) domain at its C-terminus. The gain-of-function mutant allele chs3-2D exhibits severe dwarfism and constitutively activated defense responses, including enhanced resistance to virulent pathogens, high defence marker gene expression, and salicylic acid accumulation. To search for novel regulators involved in CHS3-mediated immune signaling, we conducted suppressor screens in the chs3-2D and chs3-2D pad4-1 genetic backgrounds. Alleles of sag101 and eds1-90 were isolated as complete suppressors of chs3-2D, and alleles of sgt1b were isolated as partial suppressors of chs3-2D pad4-1. These mutants suggest that SAG101, EDS1-90, and SGT1b are all positive regulators of CHS3-mediated defense signaling. Additionally, the TIR-type NLR-encoding CSA1 locus located genomically adjacent to CHS3 was found to be fully required for chs3-2D-mediated autoimmunity. CSA1 is located 3.9 kb upstream of CHS3 and is transcribed in the opposite direction. Altogether, these data illustrate the distinct genetic requirements for CHS3-mediated defense signaling.


Antenatal Diagnosis of Fetal Retinoid Syndrome at 20 Weeks of Gestation: A Case Report.
Isotretinoin, a synthetic derivative of vitamin A, is one of the most potent human teratogens, and is mainly utilized for the treatment of severe recalcitrant nodular acne. Retinoic acid embryopathy is well defined in the literature. The mother was referred for a fetal posterior fossa abnormality, first detected at 20 weeks of gestation. The mother used isotretinoin until 18 weeks gestation. Ultrasound examination revealed hypertelorism, cerebellar hypoplasia, vermian agenesis, truncus arteriosus, anotia, thymic aplasia, corpus callosum hypoplasia. An intrauterine diagnosis of fetal retinoid syndrome was confirmed by fetopsy after termination of pregnancy. The typical findings of fetal retinoid syndrome can be visualized with ultrasound in early second trimester.


Natural history of stage IV epithelial ovarian cancer.
In this report we present the natural history, prognostic factors, and therapeutic implications of stage IV epithelial ovarian cancer (EOC). We reviewed 192 patients with stage IV EOC as defined in 1985 by the International Federation of Gynecology and Obstetrics. The site of stage IV-defining disease was cytologically positive pleural effusion in 63 patients, liver in 50 patients, lymph nodes in 26 patients, lung in six patients, other sites in 15 patients, and disease at multiple stage IV-defining metastatic sites in 32 patients. Surgery was performed before chemotherapy in 169 patients; 25 patients (14.8%) were left with only microscopic residual disease or less than 2 cm of macroscopic residual disease. The overall response rate to chemotherapy was 56%; the complete response rate was 18%. The median progression-free survival was 7.1 months, and the median overall survival was 13.4 months. The median overall survival of patients with positive pleural effusions only was 13.4 months as compared with 10.5 months for patients with visceral disease only, but this difference was not statistically significant. The 5-year survival rate was 7.6%, with only six patients surviving more than 5 years. Univariate and multivariate analysis showed that two parameters were associated with a shorter survival time: visceral involvement (lung or liver) and diagnosis before 1984. Patients with stage IV EOC initially respond to chemotherapy as often as those with less advanced disease, but the long-term prognosis is very poor. The size of residual disease is not a prognostic factor in this group of patients, and, therefore, the role of debulking surgery in these patients needs to be reconsidered.


Locomotion diagnostics: Some neuromuscular and robotic aspects.
Some aspects of neuromuscular function evaluation in fast sports locomotion are presented. The procedure of locomotion diagnostics and the underlying principles are discussed, and experimental data for their support are given. These data concern the evaluation of locomotor skill and of muscle fatigue. The approach processes some features similar to robotic systems study and is potentially applicable to other (ergonomic, medical) areas as well. Among the major limitations of the methodology are a relatively crude representation of the neuromuscular system, with only a few major muscles (and only in the lower extremities) monitored, and the fact that the EMG gives an indication of an actively generated muscle force only, and not of significant elastic force components.


Reproductive and obstetrical outcomes with the overall survival of fertile-age women treated with fertility-sparing surgery for borderline ovarian tumors in Sweden: a prospective nationwide population-based study.
To assess the efficacy of fertility-sparing surgery (FSS) in terms of reproductive outcomes by following FSS for borderline ovarian tumors (BOTs) and comparing the safety of FSS versus radical surgery (RS). Nationwide cohort study based on prospectively recorded data. Sweden. All women of reproductive age (18-40 years) treated in Sweden for stage I BOT with the use of FSS or RS from 2008 to 2015, identified in the Swedish Quality Registry for Gynecologic Cancer (SQRGC). FSS or RS. Reproductive outcomes: natural conception, use of assisted reproductive technology (ART), live birth and obstetrical outcomes. Safety outcome: overall survival (OS) rates, comparing women undergoing FSS versus RS. The FSS cohort was linked to the Swedish Medical Birth Register to identify all women who had given birth after FSS and to obtain detailed obstetrical data. For information on ART treatment, the National Quality Registry for Assisted Reproduction was consulted. OS rate comparisons were conducted by means of Kaplan-Meier estimates. Of the 277 women with BOTs, 213 (77%) underwent FSS, 183 (86%) unilateral salpingo-oophorectomy, and 30 (14%) cystectomy. Following FSS, 50 women gave birth to 62 healthy children, 8% of which were preterm. Only 20 (9%) of the women underwent ART treatment. OS was similar in women treated with FSS and RS. Natural fertility was maintained after FSS; only 9% required ART treatment. FSS was also deemed to be equivalent to RS regarding survival outcome.


A label-free electrochemical test for DNA-binding activities of tumor suppressor protein p53 using immunoprecipitation at magnetic beads.
In this paper we extend the application area of the label-free structure-sensitive electrochemical DNA sensing with mercury-based electrodes which is for the first time used, in combination with immunoprecipitation at magnetic beads (MB), for the probing of DNA interactions with tumor suppressor protein p53. The technique relies on capture of the p53-DNA complexes at MB via anti-p53 antibodies, followed by salt-induced dissociation of linear DNA from the complex and its voltammetric detection. Competitive binding of p53 to various plasmid DNA substrates, including lin or scDNAs with or without a specific target site, can easily be followed by ex situ electrochemical analysis of DNA recovered from the immunoprecipitated complexes. Compared to gel electrophoresis which is usually applied to analyze different plasmid DNA forms and their complexes with proteins, the electrochemical detection is faster and allows simpler quantitation of DNA containing free ends at submicrogram levels. We demonstrate applicability of the proposed technique to monitor different DNA-binding activities of wild type and mutant p53 proteins.


Safety of robotic-assisted gynecologic surgery and early hospital discharge in elderly patients.
A minimally invasive surgical approach has proven to decrease peri- and postoperative complications and shorten duration of hospital stay; however, there are limited data evaluating the safety of robotic-assisted surgery and early hospital discharge in the elderly population. Because age is a well-known, independent risk factor for perioperative morbidity and gynecologists treat many elderly patients, this is an important area of study. The objective of the study was to evaluate discharge timing and surgical outcomes in elderly compared with younger patients undergoing robotic-assisted gynecologic surgery. This was a retrospective cohort study of all patients who underwent robotic-assisted gynecologic surgery at a high-volume, single institution from January 2013 through May 2016. Demographic information, discharge timing, and peri- and postoperative outcomes were compared for patients <65 years with those ≥65 years using univariate and multivariate analyses. There were 2757 patients included, with 2521 <65 years and 236 ≥65 years. Median age of the younger group was 42 years, while the median age of the elderly group was 69 years. Elderly patients had a higher body mass index (kilograms per square meter) (28 vs 26, P < .001) and higher American Society of Anesthesia classification (P < .001). Elderly were more likely to have malignancy as the indication for surgery (68% vs 11%, P < .001) and to undergo hysterectomy (81% vs 38%, P < .001) or surgery with lymph node dissection (44.5% vs 7.1%, P < .001). Elderly patients had a higher incidence of intraoperative complications (9% vs 4.6%, P = .002) and longer median hospital stay (17 vs 7 hours, P < .001) compared with younger patients. Same-day discharge was more common in younger patients (76% vs 45%, P < .001), and elderly patients were more likely to have admissions lasting >23 hours (13% vs 3%, P < .001) on univariate and multivariate analysis. Analysis of postoperative outcomes included 2023 patients with available postoperative data (80% of total population) (1794 <65 years, 229 ≥ 65 years). There were no differences between elderly and younger patients in overall postoperative complications, reoperations, intensive care unit admissions, emergency room visits, or hospital readmission within 6 weeks of surgery. Despite having more preoperative risk factors and more surgically complex procedures, elderly patients undergoing robotic-assisted gynecologic surgery had similar postoperative complication rates, and almost half of elderly patients were safely discharged the day of surgery. Our data suggest that robotic-assisted gynecologic surgery and early hospital discharge are safe in elderly patients.


Maternal stress in pregnancy affects myelination and neurosteroid regulatory pathways in the guinea pig cerebellum.
Prenatal stress predisposes offspring to behavioral pathologies. These may be attributed to effects on cerebellar neurosteroids and GABAergic inhibitory signaling, which can be linked to hyperactivity disorders. The aims were to determine the effect of prenatal stress on markers of cerebellar development, a key enzyme in neurosteroid synthesis and the expression of GABAA receptor (GABAAR) subunits involved in neurosteroid signaling. We used a model of prenatal stress (strobe light exposure, 2 h on gestational day 50, 55, 60 and 65) in guinea pigs, in which we have characterized anxiety and neophobic behavioral outcomes. The cerebellum and plasma were collected from control and prenatally stressed offspring at term (control fetus: n = 9 male, n = 7 female; stressed fetus: n = 7 male, n = 8 female) and postnatal day (PND) 21 (control: n = 8 male, n = 8 female; stressed: n = 9 male, n = 6 female). We found that term female offspring exposed to prenatal stress showed decreased expression of mature oligodendrocytes (∼40% reduction) and these deficits improved to control levels by PND21. Reactive astrocyte expression was lower (∼40% reduction) following prenatal stress. GABAAR subunit (δ and α6) expression and circulating allopregnanolone concentrations were not affected by prenatal stress. Prenatal stress increased expression (∼150-250% increase) of 5α-reductase type-1 mRNA in the cerebellum, which may be a neuroprotective response to promote GABAergic inhibition and aid in repair. These observations indicate that prenatal stress exposure has marked effects on the development of the cerebellum. These findings suggest cerebellar changes after prenatal stress may contribute to adverse behavioral outcomes after exposure to these stresses.


Phospholipase A2 is an Inflammatory Predictor in Cardiovascular Diseases: Is there any Spacious Room to Prove the Causation?
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme family of phospholipase A2 produced by the inflammatory cell in atherosclerotic plaque. It is transported in the circulation, attached mainly to low-density lipoprotein-cholesterol (LDL-C). It hydrolyzes glycerophospholipids particularly fatty acids at the sn-2 position and produces numerous bioactive lipids; and leads to endothelial dysfunction, atherosclerotic plaque inflammation, and development of the necrotic core in plaques. There are two kinds of phospholipase A2, namely: secretory phospholipase A2 (sPLA2) and Lp- PLA2. They are deemed as evolving predictors of cardiovascular disease (CVD) risk in hospitaland population-based studies, including healthy subjects, acute coronary syndromes (ACS) and patients with CVD. Unfortunately, Lp-PLA2 inhibitor (darapladib) and s-PLA2 inhibitor (varespladib methyl) failed to prove to lower the risk of composite CVD mortality, myocardial infarction and stroke in those with stable CVD and ACS. Herein, we describe the explanation based on the existing data why there is still a discrepancy among them. So, it highlights the opinion that phospholipase A2 is merely the inflammatory biomarkers of CVD and playing an important role in atherosclerosis. Further, there is more spacious room to prove the causation.


Evaluation of mechanical and adhesion properties of glass ionomer cement incorporating nano-sized hydroxyapatite particles.
Glass ionomer cement is a widely used luting agent for indirect restorations but presents inferior mechanical properties compared to resin cement due to its low elastic modulus. This study evaluated the mechanical and adhesion properties of glass ionomer luting cements reinforced with nano-sized hydroxyapatite particles (HA). The nano-sized HA particles were synthesized using the co-precipitation technique and the resulting precipitate was characterized using X-ray diffraction analysis (XRD), field emission scanning electron (FESEM) and transmission electron microscopy (TEM). HA particles were incorporated into the glass powder (FUJI I, GC) and the luting agent was manipulated in a liquid to powder ratio of 3:1 into 6% by weight after determining the best ratio. The flexural strength of the luting agent and shear bond strength of dentin were analyzed and compared to other luting agents namely, (a) glass ionomer (FUJI I), (b) resin-modified glass ionomer (RelyX Luting Plus) and (c) adhesive resin cement (RelyX U200). Failure types after debonding from dentin were evaluated under SEM. Flexural strength and bond strength data were analyzed using one-way ANOVA and Tukey's tests (alpha = 0.001). Addition of 6 w % HA particles in the range of 80-150 nm enhanced the flexural strength (30.97 ± 5.9 versus 11.65 ± 5.63) and shear bond strength (0.97 ± 0.41 versus 0.39 ± 0.16) of a conventional glass ionomer luting agent significantly compared to the non-reinforced ones when manipulated at a liquid to powder ratio of 3:1 (P < 0.001). While conventional glass ionomer, HA-reinforced glass ionomer and resin-modified glass ionomer specimens showed exclusively mixed type of failures, adhesive resin cement showed cohesive failures within the resin cement. Increased mechanical and adhesion potential of the experimental glass ionomer luting agent after incorporation of HA particles could expand the scope of application of this cement.


Ultrasound-guided FNA cytology of groin lymph nodes improves the management of squamous cell carcinoma of the vulva: Results from a comparative cytohistological study.
Lymph node metastases represent the most important negative prognostic predictor in vulvar carcinoma. Therefore, an accurate preoperative assessment of suspicious lymph nodes would be fundamental for a personalized therapy. The aim of this article was to assess the reliability of ultrasound-guided fine-needle aspiration cytology (FNAC) in the preoperative assessment of nodal metastatic disease in 43 patients with vulvar cancer. In total, 43 FNAC specimens of clinicoradiologically suspicious lymph nodes with corresponding nodal resection specimens were collected from 2016 to 2018 at Catholic University Hospital in Rome. Cytohistologic correlation was performed. Patients were treated with wide local excision of the vulvar mass followed by bilateral inguinofemoral lymphadenectomy and radiotherapy if the tumor involved a lymph node or the vulvar margins. Cytologic examination agreed with histology in 37 of 43 cases (86.04%). The authors observed a positive FNAC result in 14 of 20 histologically confirmed metastatic lymph nodes, 6 false-negative cases, and no false-positive results. The sensitivity and specificity of cytological examination were 76.92% and 100%, respectively. All patients with FNAC-positive results showed metastatic disease in other surgically resected inguinofemoral nodes. Eleven of 29 patients (37.9%) with FNAC-negative results also showed metastatic disease in subsequent lymphadenectomy specimens, but the extent of metastases was always <1 cm (range, 0.1-0.6 cm). FNAC of suspicious lymph nodes represents a useful tool in the management of patients with vulvar cancer. A positive result enables the surgeon to immediately perform a bilateral inguinofemoral lymphadenectomy thus avoiding an unnecessary sentinel lymph node sampling. Finally, FNAC can also predict the presence and extent of metastatic disease in other surgically resected inguinofemoral lymph nodes.


Intra-oral air mercury released from dental amalgam.
Intra-oral air was analyzed for mercury (Hg) vapor concentration in 46 subjects, 35 of whom had dental amalgam restorations. Measurements were made with a Jerome Hg detector both before and ten min after chewing stimulation. Subjects with dental amalgams had unstimulated Hg vapor concentrations that were nine times greater than basal levels in control subjects with no amalgams. Chewing stimulation in subjects with amalgams increased their Hg concentration six-fold over unstimulated Hg levels, or a 54-fold increase over levels observed in control subjects. Concentrations of Hg measured in intra-oral air larger than those reported in expired air were attributed to the rate and direction of air passage across amalgam surfaces. There were significant correlations between Hg vapor released into intra-oral air after chewing stimulation and the numbers and types of amalgam restorations. It is concluded that intraoral air is a reliable physiological indicator of Hg released from dental amalgam that may reflect a major source of chronic Hg exposure.


Somatostatin receptor scintigraphy useful in stage I-II Hodgkin's disease: more extended disease identified.
Somatostatin receptor (SS-R) scintigraphy successfully shows primary cancers and metastases in patients with a variety of SS-R-positive tumours. In vitro studies have shown that SS-Rs are present in lymph nodes from patients with Hodgkin's disease (HD). We performed a prospective study in 126 newly diagnosed patients with HD and compared the results of SS-R scintigraphy with conventional staging procedures, i.e. physical examination, computerized tomography (CT) scanning and other imaging techniques. We report positive scintigraphy in all patients. The lesion-related sensitivity was 94% and varied from 98% for supradiaphragmatic lesions to 67% for infradiaphragmatic lesions. In comparison with CT scanning and ultrasonography, SS-R scintigraphy provided superior results for the detection of Hodgkin's localizations above the diaphragm. In the intra-abdominal region, the CT scan was more sensitive than the SS-R scan. A false-positive scan was rarely seen. In stages I and II supradiaphragmatic HD patients, SS-R scintigraphy detected more advanced disease in 18% (15 out of 83) of patients, resulting in an upstaging to stage III or IV, thus directly influencing patient management. Our data would support the validity of SS-R scanning as a powerful imaging technique for the staging of patients with HD.


Influence of the A3669G Glucocorticoid Receptor Gene Polymorphism on the Metabolic Profile of Pediatric Patients with Congenital Adrenal Hyperplasia.
Background. Pediatric CAH patients have an increased risk of cardiovascular disease, and it remains unknown if genetic predisposition is a contributing factor. Glucocorticoid receptor gene (NR3C1) polymorphisms are associated with an adverse metabolic profile. Our aim was to analyze the association between the NR3C1 polymorphisms and the metabolic profile of pediatric CAH patients. Methods. Forty-one patients (26SW/15SV) received glucocorticoid (GC) replacement therapy to achieve normal androgen levels. Obesity was defined by BMI ≥ 95th percentile. NR3C1 alleles were genotyped, and association analyses with phenotype were done with Chi-square, t-test, and multivariate and regression analysis. Results. Obesity was observed in 31.7% of patients and was not correlated with GC doses and treatment duration. Z-score BMI was positively correlated with blood pressure, triglycerides, LDL-c levels, and HOMA-IR. NR3C1 polymorphisms, BclI and A3669G, were found in 23.1% and 9.7% of alleles, respectively. A3669G carriers presented higher LDL-c levels compared to wild-type subjects. BclI-carriers and noncarriers did not differ. Conclusion. Our results suggest that A3669G-polymorphism could be involved with a susceptibility to adverse lipid profile in pediatric CAH patients. This study provides new insight into the GR screening during CAH treatment, which could help to identify the subgroup of at-risk patients who would most benefit from preventive therapeutic action.


The role of gap junction proteins in the development of neural network functional topology.
Gap junctions (GJs) provide a common form of intercellular communication in most animal cells and tissues, from Hydra to human, including electrical synaptic signalling. Cell coupling via GJs has an important role in development in general, and in neural network development in particular. However, quantitative studies monitoring GJ proteins throughout nervous system development are few. Direct investigations demonstrating a role for GJ proteins by way of experimental manipulation of their expression are also rare. In the current work we focused on the role of invertebrate GJ proteins (innexins) in the in vitro development of neural network functional topology, using two-dimensional neural culture preparations derived from the frontal ganglion of the desert locust, Schistocerca gregaria. Immunocytochemistry and quantitative real-time PCR revealed a dynamic expression pattern of the innexins during development of the cultured networks. Changes were observed both in the levels and in the localization of expression. Down-regulating the expression of innexins, by using double-strand RNA for the first time in locust neural cultures, induced clear changes in network morphology, as well as inhibition of synaptogenesis, thus suggesting a role for GJs during the development of the functional topology of neuronal networks.


Postgraduate education in medical ethics in Japan.
The objective of this paper was to investigate what kind of postgraduate education in medical ethics medical residents in Japan receive and what they want for ethical education and guidelines. Sixteen teaching hospitals that provide a general internal medicine residency programme in Japan were used (145 medical residents working at the departments of general internal medicine). A total of 114 residents participated in our survey, yielding a response rate of 79%. Of these, 28% received education in medical ethics more than once a month; 24% were offered it only when ethical problems were involved in actual patient care; and 18% answered that opportunities were very rare and sporadic. A full 30% had received no education in medical ethics at all. Many residents (71%) learned medical ethics from individual supervising doctors. A majority of the residents had been taught about informed consent (79%) and doctor-patient relationships (54%); 46% had learned about the appropriateness of truth telling and of ethical decisions regarding withholding and withdrawing a life-sustaining treatment, respectively. A total of 85 residents (75%) wanted to have more comprehensive education in medical ethics, 13% could not decide, and 12% did not want it. Many (66%) thought that both doctors and ethical philosophers should jointly teach medical ethics in postgraduate residency programmes. The results suggest that many residents desire more comprehensive and interdisciplinary education in medical ethics and educators in Japan should aim to develop education programmes to meet these desires.


Ligand binding and activation of the secretin receptor, a prototypic family B G protein-coupled receptor.
The secretin receptor is a prototypic member of family B G protein-coupled receptors that binds and responds to a linear 27-residue peptide natural ligand. The carboxyl-terminal region of this peptide assumes a helical conformation that occupies the peptide-binding cleft within the structurally complex disulphide-bonded amino-terminal domain of this receptor. The amino terminus of secretin is directed toward the core helical bundle domain of this receptor that seems to be structurally distinct from the analogous region of family A G protein-coupled receptors. This amino-terminal region of secretin is critical for its biological activity, to stimulate Gs coupling and the agonist-induced cAMP response. While the natural peptide ligand is known to span the two key receptor domains, with multiple residue-residue approximation constraints well established, the orientation of the receptor amino terminus relative to the receptor core helical bundle domain is still unclear. Fluorescence studies have established that the mid-region and carboxyl-terminal end of secretin are protected by the receptor peptide-binding cleft and the amino terminus of secretin is most exposed to the aqueous milieu as it is directed toward the receptor core, with the mid-region of the peptide becoming more exposed upon receptor activation. Like other family B peptide hormone receptors, the secretin receptor is constitutively present in a structurally specific homo-dimeric complex built around the lipid-exposed face of transmembrane segment four. This complex is important for facilitating G protein association and achieving the high affinity state of this receptor.


[Role of neuropeptides and "pain substances" in the formation of humoral mechanisms of experimental and postoperative pain].
Humoral mechanisms of pain caused by different factors vary. The authors compare blood concentrations of "painful substances" in experimental dogs and in patients suffering from postoperative pain relieved by electroacupuncture for assessing the role of these substances: serotonin, histamine, prostaglandin F2 alpha (PGF), and neuropeptides beta-endorphine, methionine- and leucine-enkephalines. Serotonin, histamine, and PGF participated in the nociception process in an equal measure both in dogs and humans. Notable differences were observed for neuropeptides, which can be explained by species-specific differences and by probable contribution of other neuropeptides to mechanisms of experimental and postoperative pain.


Serum 25-hydroxy vitamin D status is not related to osteopenia/osteoporosis risk in colorectal cancer survivors.
The incidence of colorectal cancer increases with vitamin D deficiency as shown in recently published studies. In addition, prospective investigations have indicated that low vitamin D levels may be associated with increased mortality of colorectal cancer, especially in stage III and IV cases. However, the exact incidence of vitamin D deficiency and the relation between vitamin D deficiency and osteopenia/osteporosis is still not known. The aim of this study is to identify severity of vitamin D deficiency and absolute risk factors of osteopenia/osteoporosis in colorectal cancer survivors. A total of 113 colorectal cancer survivors treated with surgery and/or chemotherapy ± radiotherapy were recruited from medical oncology outpatient clinics during routine follow-up visits in 2012-2013. Bone mineral densitometry (BMD) was performed, and serum 25-OH vitamin D levels were also checked on the same day of the questionnaire. The patients was divided into 2 groups, group A with normal BMD and group B with osteopenia/osteoporosis. The median age of the study population was 58 (40-76). Thirty (30.0%) were female, whereas 79 (70.0%) were male. The median follow-up was 48 months (14-120 months). Vitamin D deficiency was found in 109 (96.5%); mild deficiency (20-30 ng/ml) in 19 (16.8%), moderate deficiency (10-20 ng/ml) in 54 (47.8%) and severe deficiency (<10 ng/ml) in 36 (31.9%). Osteopenia was evident in 58 (51.4%) patients whereas osteoporosis was noted in 17 (15.0%) . Normal BMD was observed in 38 (33.6%). No apparent effects of type of surgery, presence of stoma, chemotherapy, radiotherapy and TNM stage were found regarding the risk of osteopenia and osteoporosis. Also, the severity of the vitamin D deficiency had no effect in the risk of osteopenia and osteporosis (p=0.93). In female patients, osteopenia/osteoporosis were observed in 79.5% patients as compared to 60.7% of male patients (p=0.04). In our study, vitamin D deficiency and osteopenia/osteoporosis was observed in 96.5% and 66.4% of colorectal cancer survivors, respectively. There is no defined absolute risk factor of osteopenia and osteoporosis in colorectal cancer survivors. To our knowledge, in the literature, our study is the first to evaluate all the risk factors of osteopenia and osteoporosis in colorectal cancer survivors.


Assessment of atrial electromechanical delay and P wave dispersion in patients with chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is associated with atrial fibrillation (AF) and reduced forced expiratory volume (FEV1) is an independent predictor for new onset AF. The aims of this study were (1) to analyze the atrial electromechanical delay (AEMD) and P wave dispersion which are two predictors of AF development in patients with COPD and without any cardiovascular disease, and (2) to assess the relationship of those with pulmonary functions as quantified by FEV1 measurements. The study included 41 patients with COPD (33 male; mean age: 51 years) and 32 healthy controls. P wave dispersion was calculated as the difference between the maximum and minimum P wave duration in a 12-lead surface electrocardiography (ECG) recording. AEMD, defined as the time interval from the P wave onset on the ECG to the initiation of the late diastolic (Am) wave using a tissue Doppler examination, was measured from the lateral mitral annulus (LAEMD), septal annulus (SAEMD), and tricuspid lateral annulus (TAEMD). P wave dispersion was significantly longer in the COPD group than those in the controls (76±19 ms vs. 45±10 ms; p<0.001). All of the AEMD measurements demonstrated significant prolongation in patients with COPD (LAEMD: 74±9 ms vs. 64±11 ms; SAEMD: 66±10 ms vs. 57±12 ms; and TAEMD: 65±9 ms vs. 46±7 ms; p<0.001 for all). The only correlation with FEV1 was observed in the TAEMD values of the COPD group (rs: -401; p<0.009). Both P wave dispersion and AEMD parameters were significantly longer in COPD patients without any established structural or functional cardiac abnormalities, indicating an increased tendency for AF development, beginning from the initial stages of the disease.


The solution structures of two human IgG1 antibodies show conformational stability and accommodate their C1q and FcγR ligands.
The human IgG1 antibody subclass shows distinct properties compared with the IgG2, IgG3, and IgG4 subclasses and is the most exploited subclass in therapeutic antibodies. It is the most abundant subclass, has a half-life as long as that of IgG2 and IgG4, binds the FcγR receptor, and activates complement. There is limited structural information on full-length human IgG1 because of the challenges of crystallization. To rectify this, we have studied the solution structures of two human IgG1 6a and 19a monoclonal antibodies in different buffers at different temperatures. Analytical ultracentrifugation showed that both antibodies were predominantly monomeric, with sedimentation coefficients s20,w (0) of 6.3-6.4 S. Only a minor dimer peak was observed, and the amount was not dependent on buffer conditions. Solution scattering showed that the x-ray radius of gyration Rg increased with salt concentration, whereas the neutron Rg values remained unchanged with temperature. The x-ray and neutron distance distribution curves P(r) revealed two peaks, M1 and M2, whose positions were unchanged in different buffers to indicate conformational stability. Constrained atomistic scattering modeling revealed predominantly asymmetric solution structures for both antibodies with extended hinge structures. Both structures were similar to the only known crystal structure of full-length human IgG1. The Fab conformations in both structures were suitably positioned to permit the Fc region to bind readily to its FcγR and C1q ligands without steric clashes, unlike human IgG4. Our molecular models for human IgG1 explain its immune activities, and we discuss its stability and function for therapeutic applications.


Stereospecific Allylic Functionalization: The Reactions of Allylboronate Complexes with Electrophiles.
Allylboronic esters react readily with carbonyls and imines (π-electrophiles), but are unreactive toward a range of other electrophiles. By addition of an aryllithium, the corresponding allylboronate complexes display enhanced nucleophilicity, enabling addition to a range of electrophiles (tropylium, benzodithiolylium, activated pyridines, Eschenmoser's salt, Togni's reagent, Selectfluor, diisopropyl azodicarboxylate (DIAD), MeSX) in high regio- and stereocontrol. This protocol provides access to key new functionalities, including quaternary stereogenic centers bearing moieties such as fluorine and the trifluoromethyl group. The allylboronate complexes were determined to be 7 to 10 orders of magnitude more reactive than the parent boronic ester.


Chlamydia trachomatis testing among young people: what is the role of stigma?
To reach young people for Chlamydia trachomatis (CT) testing, new web-based strategies are used to offer testing via young people's sexual and social networks. The success of such peer-driven strategies depends on whether individuals disclose their own testing and encourage others to get tested. We assessed whether public- and self-stigma would hamper these behaviours, by comparing anticipations and experiences relating to these issues in young men and women who already tested or never tested for CT. Participants were recruited at an STI clinic and two schools in the Netherlands. Semi-structured interviews were analysed from 23 sexually active heterosexual young people between 16-24 years using qualitative content analysis with a framework approach. Both tested and never tested participants perceived public stigma and anticipated shame and self-stigma in relation to testing. Maintaining good health was identified as main reason for testing. Never tested and tested participants anticipated that they would feel shame and receive stigmatizing reactions from people outside their trusted network if they would disclose their testing, or encourage them to test. From a selected group of trusted peers, they anticipated social support and empathy. When tested participants disclosed their testing to trusted peers they did not experience stigma. Due to the fact that no one disclosed their testing behaviour to peers outside their trusted network, stigma was avoided and therefore tested participants reported no negative reactions. Similarly, regarding the encouragement of others to test, most tested participants did not experience negative reactions from sex partners and friends. Young people perceive public stigma and anticipate self-stigma and shame in relation to CT testing, disclosure and encouraging others to test. People do test for CT, including those who anticipate stigma. To avoid stigmatizing reactions, stigma management strategies are applied, such as selective disclosure and the selective encouragement of others to test (i.e. only in a small trusted peer network). Care strategies that deploy sexual and social networks of individuals can reach into small networks surrounding a person. These strategies could be improved by exploring methods to reach high-risk network members outside the small trusted circle of a person.


Failure of autogenous reversed saphenous vein femoropopliteal grafting: pathophysiology and prevention.
As part of a study of various clinical, pathologic, and hemodynamic factors on both short- and long-term patency of autogenous reversed saphenous vein femoropopliteal bypass grafts, an early and recent series of patients from Yale University School of Medicine is compared with four other index series. Review and comparison reveals a well-recognized pattern of graft failure that occurs in three definable periods. The closure rate differs between periods and among series and allows a delineation of the responsible factors. Improvement in long-term cumulative patency rate depends on an understanding of the factors responsible for vein graft failure and the methods for their elimination or control.


N-methyl-D-aspartate-induced excitation and sensitization of normal and inflamed nociceptors.
The present study investigates the contribution of peripheral N-methyl-D-aspartate (NMDA) receptors to acute nociception and persistent inflammatory pain in the rat. Immunohistochemical localization of the NMDA receptor one (NMDAR1) subunit demonstrates that 47% of unmyelinated axons in the normal digital nerve are positively labeled. In concert with the overall progression of inflammation following injection of complete Freund's adjuvant (CFA) in the hind paw, a significant increase in the proportion of NMDAR1-labeled unmyelinated digital axons occurs at 2 and 7, but not 14 days following hind-paw inflammation. In behavioral studies, we confirm an increased mechanical sensitivity in CFA-injected hind paws. Furthermore, activation of NMDA receptors following intraplantar NMDA (1.0 mM) in normal animals results in a mechanical sensitivity similar to that observed in inflamed animals. Conversely, a low concentration of NMDA (0.5 mM) that has little affect on mechanical thresholds in normal animals produces a significant increase in mechanical sensitivity in the inflamed state. CFA-induced mechanical sensitivity involves NMDA-receptor activation demonstrated by the observation that injection of MK-801 alone into the inflamed hind paw returns mechanical sensitivity to normal (pre-inflammation) levels. In single-unit studies, there is a dose-dependent increase in NMDA-induced nociceptor activity in both normal and inflamed skin, but the amount of NMDA required to induce activation is reduced in inflamed skin. In addition, NMDA-induced discharge rates and percentage of NMDA-activated nociceptors are significantly increased in inflamed compared with normal skin, and this activation can be blocked by co-administration of MK-801. Exposure of nociceptors in normal skin to 1 mM NMDA sensitizes the units to reapplication of NMDA and to heat. Nociceptors that demonstrate sensitization to heat in persistent inflammation show an enhanced sensitization when exposed to exogenous NMDA. Thus, peripheral NMDA receptors not only play an important role in modulating the responses of nociceptors in normal skin, but their upregulation and activation on peripheral nociceptors contributes significantly to the mechanical sensitivity and heat sensitization that accompanies persistent inflammation.


Superior myocardial preservation with HTK solution over Celsior in rat hearts with prolonged cold ischemia.
Increasing allograft ischemic time is a significant risk factor for mortality following heart transplantation (HTx). The purpose of this study was to evaluate the protective effects of histidine-tryptophan-ketoglutarate (HTK) and Celsior (CEL) using a rat HTx model with prolonged cold storage. The hearts were excised from donor rats, stored in cold preservation solution for either 6 or 18 hours, and heterotopically transplanted into syngeneic recipients. Serum creatine phosphokinase (CPK), serum troponin I, graft-infiltrating cells, graft mRNA levels for inflammatory mediators, and tissue adenosine triphosphate (ATP) levels were analyzed, as markers of graft injury. The recipients of grafts stored in HTK for 18 hours of prolonged cold ischemia had lower levels of serum CPK and tissue malondialdehyde, less upregulation of the mRNAs for IL-6 and inducible nitric oxide synthase, less apoptosis, and higher ATP levels than those receiving grafts stored in CEL and Saline. Cardiac contraction 3 hours after reperfusion was observed in 43% of the cardiac grafts stored in HTK for 18 hours, while no cardiac wall movement was seen in grafts stored in either saline or CEL. Cold storage in HTK exhibited superior protective effects against prolonged cold ischemia in a syngeneic rat transplantation model.


Commercial Optical and Acoustic Sensor Performances under Varying Turbidity, Illumination, and Target Distances.
Acoustic and optical sensing modalities represent two of the primary sensing methods within underwater environments, and both have been researched extensively in previous works. Acoustic sensing is the premier method due to its high transmissivity in water and its relative immunity to environmental factors such as water clarity. Optical sensing is, however, valuable for many operational and inspection tasks and is readily understood by human operators. In this work, we quantify and compare the operational characteristics and environmental effects of turbidity and illumination on two commercial-off-the-shelf sensors and an additional augmented optical method, including: a high-frequency, forward-looking inspection sonar, a stereo camera with built-in stereo depth estimation, and color imaging, where a laser has been added for distance triangulation. The sensors have been compared in a controlled underwater environment with known target objects to ascertain quantitative operation performance, and it is shown that optical stereo depth estimation and laser triangulation operate satisfactorily at low and medium turbidites up to a distance of approximately one meter, with an error below 2 cm and 12 cm, respectively; acoustic measurements are almost completely unaffected up to two meters under high turbidity, with an error below 5 cm. Moreover, the stereo vision algorithm is slightly more robust than laser-line triangulation across turbidity and lighting conditions. Future work will concern the improvement of the stereo reconstruction and laser triangulation by algorithm enhancement and the fusion of the two sensing modalities.


The Effect of Three-Dimensional Whole, Major, and Small Vasculature on Mouse Brain Strain Under Both Diffuse and Focal Brain Injury Loading.
Blood vessels are much stiffer than brain parenchyma and their effects in finite element (FE) brain models need to be investigated. Despite the publication of some comprehensive three-dimensional (3D) brain vasculature models, no mechanical model exists for the mouse brain vasculature. Moreover, how the vasculature affects the mechanical behavior of brain tissue remains controversial. Therefore, we developed FE mouse brain models with detailed 3D vasculature to investigate the effect of the vasculature on brain strains under both diffuse (closed-head impact) and focal injury (controlled cortical impact (CCI)) loading, two commonly laboratory models of traumatic brain injury. The effect of the vasculature was examined by comparing maximum principal strain in mouse brain FE models with and without the vasculature. On average, modeling comprehensive vasculature under diffuse injury loading reduced average brain strain predictions by 32% with nonlinear elastic properties. Nearly three-fourths of the 32% strain reduction was attributable to the effects of the major branches of the vasculature. Meanwhile, during focal open-skull CCI injury loading, the contribution of the vasculature was limited, producing a less than 5% reduction in all cases. Overall, the vasculature, especially the major branches, increased the load-bearing capacity of the brain FE model and thus reduced brain strain predictions.


Cytologic features and clinical implications of undifferentiated carcinoma with osteoclastic giant cells of the pancreas: An analysis of 15 cases.
The cytologic features of undifferentiated pancreatic carcinoma with osteoclastic giant cells (UOC) are rarely described. Cytologic and clinicopathologic characteristics in 15 UOC fine-needle aspiration (FNA) specimens were analyzed. FNA specimens were obtained from 6 men and 8 women with a mean age of 65 years who had UOCs (head, n = 7; body, n = 3; and tail, n = 4) with a mean radiologic size 7.3 cm, and some had a cystic component (n = 9). Three cell types (osteoclastic giant cells, pleomorphic tumor giant cells, and spindled/histiocytoid cells) were observed in 12 of 15 specimens (80%); and pancreatic ductal adenocarcinoma (PDAC) was present in 11 specimens. FNA diagnoses were UOC (n = 6), PDAC (n = 5), poorly differentiated carcinoma (n = 2), "suspicious for neoplasm" (n = 1), and "negative" (n = 1). Five of 5 specimens with osteoclastic giant cells were positive for cluster of differentiation 68 (CD68) (a glycoprotein that binds to low-density lipoprotein). Pleomorphic tumor giant cells and spindled/histiocytoid cells were positive for pancytokeratin (6 of 7 specimens), CAM5.2 (2 of 3 specimens), and epithelial membrane antigen (2 of 2 specimens). INI-1 protein expression was retained in 3 of 3 specimens. The Ki-67 labeling index was assessed in 3 specimens and was 12%, 18%, and 40%; 4 of 12 resected UOCs were pure, and 8 were mixed with PDAC. One resection specimen had intraductal papillary mucinous neoplasm, and 2 had mucinous cystic neoplasms. The median overall survival (OS) of patients who had UOCs identified on FNA was 8 months (6 died [OS, 8 months; range, 2-22 months], and 8 remained alive [OS, 3 months; range, 1-27 months]), which was similar to the survival of 74 patients who had PDACs identified on FNA (OS, 15 months; P = .279) but worse than that of the 27 patients with UOCs who did not undergo FNA (OS, 92 months; P = .0135). The 3 classical UOC cell types are identifiable on FNA, making cytologic diagnosis possible if considered in the differential. A PDAC component is often also observed. The survival advantage of UOC over pure PDAC appears to be negated by FNA and requires further investigation. Cancer Cytopathol 2017;125:563-75. © 2017 American Cancer Society.


Maternal and fetal haemodynamic effects of spinal and extradural anaesthesia for elective caesarean section.
Serial haemodynamic investigations were performed in 32 women who were allocated randomly to receive either spinal or extradural anaesthesia for elective Caesarean section. Cardiac output was measured by Doppler and cross-sectional echocardiography at the aortic valve. Doppler flow velocity waveforms were recorded also from the umbilical artery. Preloading with Ringer lactate solution 1 litre increased cardiac output in both groups. After injection of bupivacaine, cardiac output remained increased in the extradural group, but decreased in the spinal group. This was associated with an increase in umbilical artery pulsatility index in the spinal group. Umbilical artery pH was less in the spinal group (7.22 vs 7.27), although no neonate was depressed at birth. The maximum percentage change in cardiac output and umbilical artery pulsatility index correlated with umbilical artery pH (r = 0.54, r = 0.72, respectively). There was no significant correlation with change in arterial pressure.


SMPD3 expression is spatially regulated in the developing embryo by SOXE factors.
During epithelial-to-mesenchymal transition (EMT), significant rearrangements occur in plasma membrane protein and lipid content that are important for membrane function and acquisition of cell motility. To gain insight into how neural crest cells regulate their lipid content at the transcriptional level during EMT, here we identify critical enhancer sequences that regulate the expression of SMPD3, a gene responsible for sphingomyelin hydrolysis to produce ceramide and necessary for neural crest EMT. We uncovered three enhancer regions within the first intron of the SMPD3 locus that drive reporter expression in distinct spatial and temporal domains, together collectively recapitulating the expression domains of endogenous SMPD3 within the ectodermal lineages. We further dissected one enhancer that is specifically active in the migrating neural crest. By mutating putative transcriptional input sites or knocking down upstream regulators, we find that the SOXE-family transcription factors SOX9 and SOX10 regulate the expression of SMPD3 in migrating neural crest cells. Further, ChIP-seq and nascent transcription analysis reveal that SOX10 directly regulates expression of an SMPD3 enhancer specific to migratory neural crest cells. Together these results shed light on how core components of developmental gene regulatory networks interact with metabolic effector genes to control changes in membrane lipid content.


HindII and HindIII restriction maps of the attphi80-tonB-trp region of the Escherichia coli genome, and location of the tonB gene.
The HindII and HindIII restriction maps of the attphi80-tonB-trp region of the Escherichia coli chromosome are presented. Analysis of phage DNAs carrying tonB mutations has allowed identification of a 1,730-base pair HindII fragment containing at least part of the tonB gene. This fragment is 4,020 base pairs from the end of trpA, with the total distance from attphi80 to trpA being 6,550 +/- 800 base pairs. Properties of hybrid plasmids containing insertions of various tonB+ restriction fragments suggest that tonB lies completely within the 1,730-base pair fragment. In addition, apparent fusions of beta-galactoside to proteins within the tonB region suggest that the entire region codes for more than one polypeptide.


A Comparison of Metacognitive Therapy in Current Versus Persistent Depressive Disorder - A Pilot Outpatient Study.
Background: Metacognitive therapy (MCT) is a modern approach with demonstrated efficacy in current major depressive disorder (MDD). The treatment aims to modify thinking styles of rumination and worry and their underlying metacognitions, which have been shown to be involved in the initiation and perpetuation of MDD. We hypothesized that metacognitive therapy may also be effective in treating persistent depressive disorder (PDD). Methods: Thirty depressed patients (15 with MDD; 15 with PDD) were included. Patients in both groups were comparable on depression severity and sociodemographic characteristics, but PDD was associated with more former treatments. Metacognitive therapy was applied by trained psychotherapists for a mean of 16 weeks. Results: We observed a significant improvement of depressive symptoms in both groups, and comparable remission rates at the end of treatment and after 6 months follow-up. Furthermore, we observed significant and similar levels of improvement in rumination, dysfunctional metacognitions, and anxiety symptoms in both groups. Limitations: The study is limited by the small sample size and a missing independent control group. The effect of the therapeutic alliance was not controlled. The quality of depression rating could have been higher. Conclusions: We demonstrated that metacognitive therapy can successfully be applied to patients with PDD. The observed results were comparable to those obtained for patients with current major depressive disorder. Further studies with larger groups and a randomized design are needed to confirm these promising initial findings.


Differential Activation of ERK Signaling in HPV-Related Oropharyngeal Squamous Cell Carcinoma.
Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) forms a distinct tumor entity with better survival clinical outcome. Numerous underlying molecular mechanisms have been postulated for differences in treatment response, but the impact of MEK/ERK signaling, a main driver of carcinogenesis in various cancers including OPSCC and key player mediating therapy resistance remains elusive. In a retrospective experimental cohort study, primary tumor samples from OPSCC patients (n = 124) were available on tissue microarrays (TMAs) and expression levels of phosphorylated ERK1/2 (pERK1/2) were detected by immunohistochemical staining. Correlations of pERK1/2 expression patterns with clinicopathological features and clinical outcome were evaluated by statistical analysis. A low pERK1/2 expression was strongly associated with HPV-related OPSCC, while primary tumors with high pERK1/2 staining showed a distinctly worse survival outcome and were associated with higher cellular differentiation. Co-activation of both ERK1/2 and AKT was a common event and was associated with unfavorable prognosis in our cohort. However, the combinatorial analysis of pAKT (Ser473) and pERK1/2 did not strengthen the predictive power of pERK1/2, suggesting that pERK1/2 plays a more significant function in OPSCC. In summary, our data provide a compelling experimental and statistical evidence that low levels of tumor cell intrinsic ERK1/2 activation contribute at least in part to the favorable outcome of HPV-related OPSCC. On the other hand, presented findings indicate that non-HPV-related OPSCC with elevated ERK phosphorylation are at high risk for treatment failure and might benefit from targeted therapy of MEK/ERK signaling.


Susceptibility to in vitro tolerance induction of adult B cells from mice with an X-linked B-cell defect.
Previous studies from this laboratory have indicated that the susceptibility to in vitro tolerance induction is restricted to B cells early in their development (12,14). In this study, a modification of the in vitro splenic focus technique was used to determine whether 2,4-dinitrophenyl (DNP)-specific splenic B cells from adult (CBA/N X DBA/2)F1 males are susceptible to in vitro tolerance induction. The results demonstrate that greater than 50% of the DNP-specific B cells in the adult F1 male are tolerizable and therefore immature by this criterion. Moreover, the findings define at least two subpopulation in adult CBA/N mice, one of which is tolerizable. These findings are consistent with the hypothesis that the lymphoid population in the adult CBA/N mouse is characteristic of a neonatal B-cell population.


Peptide-based hydrogen sulphide-releasing gels.
An aromatic peptide amphiphile was designed for delivery of the signaling gas H2S. The peptide self-assembled in water into nanofibers that gelled upon charge screening. The non-toxic gel slowly released H2S over 15 hours, and the presence of H2S in endothelial cells was verified using a fluorescent H2S probe.


A Beetle Flight Muscle Displays Leg Muscle Microstructure.
In contrast to major flight muscles in the Mecynorrhina torquata beetle, the third axillary (3Ax) muscle is a minor flight muscle that uniquely displays a powerful mechanical function despite its considerably small volume, ∼1/50 that of a major flight muscle. The 3Ax muscle contracts relatively slowly, and in flight strongly pulls the beating wing to attenuate the stroke amplitude. This attenuation leads to left-right turning in flight or wing folding to cease flying. What enables this small muscle to be so powerful? To explore this question, we examined the microstructure of the 3Ax muscle using synchrotron x-ray diffraction, optical microscopy, and immunoblotting analysis. We found that the 3Ax muscle has long (∼5 μm) myofilaments and that the ratio of thick (myosin) filaments to thin (actin) filaments is 1:5 or 1:6. These characteristics are not observed in the major flight muscles, which have shorter myofilaments (∼3.5 μm) with a smaller ratio (1:3), and instead are more typical of a leg muscle. Furthermore, the flight-muscle-specific troponin isoform, TnH, is not expressed in the 3Ax muscle. Since such a microstructure is suitable for generating large tension, the 3Ax muscle is appropriately designed to pull the wing strongly despite its small volume.


Bone regeneration with autologous biomaterial; rapid induction of vital new bone in maxillary sinus floor by platelet concentrate alone at 23x baseline (PRP23x): a case report.
To date, most clinicians and researchers have been using platelet concentrate within the range of 4x to 8x baseline. In this case report a new procedure involving strategic pooling and triple spin was developed and used to concentrate platelets to 23x baseline. The concentrate alone was infused into morselized resorbable collagen sponge, activated with calcium chloride and autologous thrombin, then placed as an autologous graft into the left sinus floor of a healthy 80-year-old woman. The floor of the sinus had approximately 2 mm of bony height. A computed tomography scan taken after 5 months showed that new bone was formed and it was as dense as native bone around the surgical site. From the computed tomography scan bone density analysis using Hounsfield Units revealed that the bone formed was D3 bone (518.3 +/- 224.9 Hounsfield Units) and it was as dense as native bone on the axial, coronal and sagittal slices. Histomorphometric analysis of 2 bone core biopsies taken after 6 months showed that 1 core had 34% bone of which 98% was vital new bone and the other core had 39% bone of which 100% was vital new bone. The height of the bone formed in the sinus floor was 12 mm. It was also characterized by good trabecular pattern and connectivity. The quality of the bone generated was such that 2 endosseous implants were placed and torqued to 30 N cm after the cores were removed.


Occupational asthma in New Zealanders: a population based study.
To examine the effect of occupation on respiratory symptoms in a randomly selected adult population aged 20-44 years. It is based on the phase II sampling of the New Zealand part of the European Community respiratory health survey. 1609 people (63.9% response rate) completed a detailed respiratory questionnaire. Of those responding, 1174 (73%) underwent skin tests and 1126 (70%) attended to undergo methacholine bronchial challenge. Current occupation was recorded and a previous occupation was also recorded if it had led to respiratory problems. 21 occupational groups were used for analysis for the five definitions of asthma wheezing in the previous 12 months; symptoms related to asthma; bronchial hyperresponsiveness (BHR); BHR with wheezing in the previous 12 months; and BHR with symptoms related to asthma. Prevalence odds ratios (ORs) were significantly increased for farmers and farm workers (OR 4.16, 95% confidence interval (95% CI) 1.33 to 13.1 for the combination of wheezing and BHR). Increased risks of prevalence of asthma were also found for laboratory technicians, food processors (other than bakers), chemical workers, and plastic and rubber workers. Workers had also been divided into high and low risk exposure categories according to relevant publications. The prevalence of wheezing was greater in the high risk group (OR 1.57, 95% CI 0.83 to 2.95) than in the low risk group. Atopy was associated with asthma, but the prevalence of atopy did not differ significantly between occupational exposure groups. The attributable risk of wheezing that occurred after the age of 15 years and that was estimated to be due to occupational exposure (based on the defined high risk group) was 1.9%, but this increased to 3.1% when farmers and food processors (other than bakers) were also included in the high risk group. This population based study has identified certain occupations significantly associated with combinations of asthmatic symptoms and BHR.


Single balloon enteroscopy for endoscopic retrograde cholangiography in patients with Roux-en-Y hepaticojejuno anastomosis.
To evaluate single balloon enteroscopy in diagnostic and therapeutic endoscopic retrograde cholangiography (ERC) in patients with Roux-en-Y hepaticojejunoanastomosis (HJA). The study took place from January 2009 to December 2011 and we retrospectively assessed 15 patients with Roux-en-Y HJA who had signs of biliary obstruction. In total, 23 ERC procedures were performed in these patients and a single balloon videoenteroscope (Olympus SIF Q 180) was used in all of the cases. A transparent overtube was drawn over the videoenteroscope and it freely moved on the working part of the enteroscope. Its distal end was equipped with a silicone balloon that was inflated by air from an external pump at a pressure of ≤ 5.4 kPa. The technical limitations or rather the parameters of the single balloon enteroscope (working length - 200 cm, diameter of the working channel - 2.8 mm, absence of Albarran bridge) showed the need for special endoscopic instrumentation. Cannulation success was reached in diagnostic ERC in 12 of 15 patients. ERC findings were normal in 1 of 12 patients. ERC in the remaining 11 patients showed some pathological changes. One of these (cystic bile duct dilation) was subsequently resolved surgically. Endoscopic treatment was initialized in the remaining 10 patients (5 with HJA stenosis, 2 with choledocholithiasis, and 3 with both). This treatment was successful in 9 of 10 patients. The endoscopic therapeutic procedures included: balloon dilatation of HJA stenosis - 11 times (7 patients); choledocholitiasis extraction - five times (5 patients); biliary plastic stent placement - six times (4 patients); and removal of biliary stents placed by us - six times (4 patients). The mean time of performing a single ERC was 72 min. The longest procedure took 110 min and the shortest took 34 min. This shows that it is necessary to allow for more time in individual procedures. Furthermore, these procedures require the presence of an anesthesiologist. We did not observe any complications in these 15 patients. This method is more demanding than standard endoscopic retrograde cholangiopancreatography due to altered postsurgical anatomy. However, it is effective, safe, and widens the possibilities of resolving biliary pathology.