Diastolic Function Evaluations by Tissue Doppler Imaging in Patients With Mitral Valve Prolapse.
Tissue Doppler imaging (TDI) is a new echocardiographic imaging technique that is believed to be superior to older conventional techniques in assessing abnormalities of cardiac function in many conditions affecting the heart. There are very limited data regarding the role of TDI in evaluating patients with mitral valve prolapse (MVP). Current study evaluates diastolic function in patients with MVP by this method. From November 2009 to April 2011, one hundred and ten adults matched for age and sex and without structural heart disease were studied in two groups, with and without MVP, at Madani Heart Center, Tabriz, Iran. TDI was performed at the basal-lateral wall and S, E, E', A, and A' velocities, as well as the E/A and E'/A' ratios were measured. Mitral annular systolic velocity and early diastolic (E') velocities were measured lateral corner of mitral valve in apical 4-chamber view. Patients with MVP had higher left atrium volume (42.31 ± 10.47 vs. 35.19 ± 9.15 cm3; P < 0.001) and deceleration time (186.70 ± 26.00 vs. 176.89 ± 20.36 ms; P = 0.03). Diastolic dysfunction, although seemed more prevalent in MVP group (14.54%) than normal subjects (5.45%), the difference was not statistically significant between groups (P = 0.11). Left atrial volume and deceleration time of mitral valve inflow was significantly higher in MVP which could be indicative of early stages of diastolic dysfunction in patients with MVP. However, larger follow-up studies are required to evaluate clinical significance of our findings in these patients.


1-(5-Carboxy- and 5-carbamoylindol-1-yl)propan-2-ones as inhibitors of human cytosolic phospholipase A2alpha: bioisosteric replacement of the carboxylic acid and carboxamide moiety.
Indole-5-carboxylic acids and -carboxamides with 3-aryloxy-2-oxopropyl residues in position 1 were previously reported to be potent inhibitors of cytosolic phospholipase A(2)alpha (cPLA(2)alpha) isolated from human platelets. In continuation of our attempts to develop novel cPLA(2)alpha inhibitors, a number of derivatives of these substances characterized by bioisosteric replacement of the carboxylic acid and carboxamide functionality, respectively, were prepared. The results of the biological evaluation of the obtained compounds enabled us to gain further insight into structural features critical for cPLA(2)alpha inhibition.


Ultrastructural and phenotypic analysis of in vitro erythropoiesis from human cord blood CD34+ cells.
Erythropoietin (EPO) induces erythropoiesis in vitro as well as in vivo, and the process of erythroid differentiation has been explored phenotypically and morphologically. However, morphological analysis of in vitro erythropoiesis of human hematopoietic progenitor cells at the ultrastructural level has not been reported before. In the present study, we have traced the ultrastructural changes of erythroid differentiation during ex vivo expansion of human cord blood (CB) CD34(+) cells in the presence of EPO by electron microscopy (EM), along with concurrent phenotypic analysis. CD34(+) cells purified from ten CBs by immunomagnetic selection were cultured in serum-free essential media in the presence of a combination of the several cytokines including EPO, thrombopoietin, flt3-ligand (FL), stem cell factor (SCF), granulocyte colony-stimulating factor, interleukin (IL)-3 and/or IL-11. Phenotypic analysis was performed by flow cytometric analysis for erythroid markers, including glycophorin C (GPC), Kell-related, glycophorin A (GPA), band 3, Lu(b), and RhD. Ultrastructural analysis was performed by electron-microscopic examination of the cultured cells stained with uranyl acetate and lead citrate. Phenotypic analysis revealed that in the absence of EPO, genuine erythroid fraction expressing the typical pattern of erythroid markers did not appear. The order of the above markers expressed in the cultured cells in the presence of EPO was GPC, Kell-related, GPA, band 3, Lu(b), and RhD, irrespective of the type of cytokine added. Of the cytokines used in combination with EPO, FL + IL-3 was the most efficient in inducing erythroid differentiation, which was followed by SCF + IL-3. EM examination demonstrated complete process of erythroid development from pronormoblasts to reticulocytes with nuclei having been extruded and mature erythrocytes. These results suggest that morphologically intact erythrocytes could be produced by ex vivo expansion of CB CD34(+) cells using EPO.


Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells.
17beta-Estradiol (E(2)) is a rapid activator of endothelial nitric oxide synthase (eNOS). The product of this activation event, NO, is a fundamental determinant of cardiovascular homeostasis. We previously demonstrated that E(2)-stimulated endothelial NO release can occur without an increase in cytosolic Ca(2+). Here we demonstrate for the first time, to our knowledge, that E(2) rapidly induces phosphorylation and activation of eNOS through the phosphatidylinositol 3 (PI3)-kinase-Akt pathway. E(2) treatment (10 ng/mL) of the human endothelial cell line, EA.hy926, resulted in increased NO production, which was abrogated by the PI3-kinase inhibitor, LY294002, and the estrogen receptor antagonist ICI 182, 780. E(2) stimulated rapid Akt phosphorylation on serine 473. As has been shown for vascular endothelial growth factor, eNOS is an E(2)-activated Akt substrate, demonstrated by rapid eNOS phosphorylation on serine 1177, a critical residue for eNOS activation and enhanced sensitivity to resting cellular Ca(2+) levels. Adenoviral-mediated EA.hy926 transduction confirmed functional involvement of Akt, because a kinase-deficient, dominant-negative Akt abolished E(2)-stimulated NO release. The membrane-impermeant E(2)BSA conjugate, shown to bind endothelial cell membrane sites, also induced rapid Akt and consequent eNOS phosphorylation. Thus, engagement of membrane estrogen receptors results in rapid endothelial NO release through a PI3-kinase-Akt-dependent pathway. This explains, in part, the reduced requirement for cytosolic Ca(2+) fluxes and describes an important pathway relevant to cardiovascular pathophysiology.


Cytotype regulation in Drosophila melanogaster: synergism between telomeric and non-telomeric P elements.
The X-linked telomeric P elements TP5 and TP6 interact synergistically with non-telomeric P elements to repress hybrid dysgenesis. In this repression, the telomeric P elements exert maternal effects, which, however, are not sufficient to establish synergism with the non-telomeric P elements. Once synergism is established, the capacity to repress dysgenesis in the offspring of a cross persists for at least two generations after removing the telomeric P element from the genotype. At the molecular level, synergism between telomeric and non-telomeric P elements is correlated with effective elimination of P-element mRNA in the germ line. Maternally transmitted mutations in the genes aubergine, piwi and Suppressor of variegation 205 [Su(var)205] block the establishment of synergism between telomeric and non-telomeric P elements, and paternally transmitted mutations in piwi and Su(var)205 disrupt synergism that has already been established. These findings are discussed in terms of a model of cytotype regulation of P elements based on Piwi-interacting RNAs (piRNAs) that are amplified by cycling between sense and antisense species.


The phosphorylation of the androgen receptor by TFIIH directs the ubiquitin/proteasome process.
In response to hormonal stimuli, a cascade of hierarchical post-translational modifications of nuclear receptors are required for the correct expression of target genes. Here, we show that the transcription factor TFIIH, via its cdk7 kinase, phosphorylates the androgen receptor (AR) at position AR/S515. Strikingly, this phosphorylation is a key step for an accurate transactivation that includes the cyclic recruitment of the transcription machinery, the MDM2 E3 ligase, the subsequent ubiquitination of AR at the promoter of target genes and its degradation by the proteasome machinery. Impaired phosphorylation disrupts the transactivation, as observed in cells either overexpressing the non-phosphorylated AR/S515A, isolated from xeroderma pigmentosum patient (bearing a mutation in XPD subunit of TFIIH), or in which cdk7 kinase was silenced. Indeed, besides affecting the cyclic recruitment of the transcription machinery, the AR phosphorylation defect favourizes to the recruitment of the E3 ligase CHIP instead of MDM2, at the PSA promoter, that will further attract the proteasome machinery. These observations illustrate how the TFIIH phosphorylation might participate to the transactivation by regulating the nuclear receptors turnover.


Antimicrobial edible apple films inactivate antibiotic resistant and susceptible Campylobacter jejuni strains on chicken breast.
Campylobacter jejuni is the leading cause of bacterial diarrheal illness worldwide. Many strains are now becoming multidrug resistant. Apple-based edible films containing carvacrol and cinnamaldehyde were evaluated for bactericidal activity against antibiotic resistant and susceptible C. jejuni strains on chicken. Retail chicken breast samples inoculated with D28a and H2a (resistant strains) and A24a (a sensitive strain) were wrapped in apple films containing cinnamaldehyde or carvacrol at 0.5%, 1.5%, and 3% concentrations, and then incubated at 4 or 23 °C for 72 h. Immediately after wrapping and at 72 h, samples were plated for enumeration of viable C. jejuni. The antimicrobial films exhibited dose- and temperature-dependent bactericidal activity against all strains. Films with ≥1.5% cinnamaldehyde reduced populations of all strains to below detection at 23 °C at 72 h. At 4 °C with cinnamaldehyde, reductions were variable for all strains, ranging from 0.2 to 2.5 logs and 1.8 to 6.0 logs at 1.5% and 3.0%, respectively. Films with 3% carvacrol reduced populations of A24a and H2a to below detection, and D28a by 2.4 logs at 23 °C and 72 h. A 0.5-log reduction was observed for both A24a and D28a, and 0.9 logs for H2a at 4 °C at 3% carvacrol. Reductions ranged from 1.1 to 1.9 logs and 0.4 to 1.2 logs with 1.5% and 0.5% carvacrol at 23 °C, respectively. The films with cinnamaldehyde were more effective than carvacrol films. Reductions at 23 °C were greater than those at 4 °C. Our results showed that antimicrobial apple films have the potential to reduce C. jejuni on chicken and therefore, the risk of campylobacteriosis. Possible mechanisms of antimicrobial effects are discussed. Apple antimicrobial films could potentially be used in retail food packaging to reduce C. jejuni commonly present on food.


[Effect of disruption of chloride conductance on the development of denervation changes in muscle fiber membranes of the rat].
A decrease in resting MP, increase in the input resistance, appearance of anode breakdown APs, and extrajunctional acetylcholine sensitivity following denervation were revealed in the rat diaphragm muscle fibres. Addition of 1 X 10(-4) M furosemide to the culture medium reduced the degree of post-denervation muscle membrane depolarization and of extrajunctional acetylcholine sensitivity, but did not prevent the changes in passive electrical properties and in firing level of the muscle fibre membrane. Chloride ions could serve as intracellular messengers responsible for the neurotrophic control of muscle membrane resting potential and membrane sensitivity to acetylcholine. The Cl- are not essential in neurotrophic regulation of the electrogenic properties of membrane.


Growth and Toxin Production of Gambierdiscus spp. Can Be Regulated by Quorum-Sensing Bacteria.
Gambierdiscus spp. are the major culprit responsible for global ciguatera fish poisoning (CFP). At present, the effects of microbiological factors on algal proliferation and toxin production are poorly understood. To evaluate the regulatory roles of quorum-sensing (QS) bacteria in the physiology of Gambierdiscus, co-culture experiments with screened QS strains were conducted in this study. Except for the growth-inhibiting effect from the strain Marinobacter hydrocarbonoclasticus, the algal host generally displayed much higher growth potential and toxin production ability with the existence of QS strains. In addition, Bacillus anthracis particularly exhibited a broad-spectrum growth enhancement effect on various Gambierdiscus types, as well as a remarkable influence on algal toxicity. The variations of algal physiological status, including growth rate, chlorophyll content, and responsive behaviors, are potential reasons for the observed positive or negative affection. This study suggests that QS bacteria regulate the algal growth and toxin production. Based on the evidence, we further speculate that QS bacteria may contribute to the site-specific distribution of CFP risk through regulating the algal host biomass and toxicity.


Harmonic generation in the opaque region of GaAs: the role of the surface and magnetic nonlinearities.
Phase-locked second and third harmonic generation in the opaque region of a GaAs wafer is experimentally observed and analyzed both in transmission and reflection. These harmonic components, which are generated close to the surface, can propagate through an opaque material as long as the pump is tuned to a region of transparency or semitransparency and correspond to the inhomogeneous solutions of Maxwell's equations with nonlinear polarization sources. We show that measurement of the angular and polarization dependence of the observed harmonic components allows one to infer the different nonlinear mechanisms that trigger these processes, including not only the bulk nonlinearity but also the surface and magnetic Lorentz contributions, which usually are either hidden by the bulk contributions or assumed to be negligible. The experimental results are compared with a detailed numerical model that takes into account these different effects, including for the first time combined linear and nonlinear material dispersions in a nonlinear Lorentz oscillator model of the bulk nonlinearities. Our results suggest that the intensity of the second harmonic signal generated by the surface can be more intense than the signal generated by the bulk. These findings have significant repercussions and are consequential in nanoscale systems, which are usually investigated using only dispersionless bulk nonlinearities, with near-complete disregard of surface and magnetic contributions and their microscopic origins.


Flavonoids as inhibitors of lens aldose reductase.
Flavonoids are effective inhibitors of lens aldose reductase. Quercetin, quercitrin, and myricitrin are significantly more potent than the previously known aldose reductase inhibitors. The inhibitory activity is of the noncompetitive type. In addition, quercitrin effectively blocks polyol accumulation in intact rat lenses incubated in medium containing high concentration of sugars.


The evolution of sex determination associated with a chromosomal inversion.
Sex determination is a fundamentally important and highly diversified biological process, yet the mechanisms behind the origin of this diversity are mostly unknown. Here we suggest that the evolution of sex determination systems can be driven by a chromosomal inversion. We show that an XY system evolved recently in particular nine-spined stickleback (Pungitius pungitius) populations, which arose from ancient hybridization between two divergent lineages. Our phylogenetic and genetic mapping analyses indicate that the XY system is formed in a large inversion that is associated with hybrid sterility between the divergent lineages. We suggest that a new male-determining gene evolved in the inversion in response to selection against impaired male fertility in a hybridized population. Given that inversions are often associated with hybrid incompatibility in animals and plants, they might frequently contribute to the diversification of sex determination systems.


Crítica al modelo centinela de vigilancia epidemiológica en la COVID-19.
To analyze the increase in sentinel cases of COVID-19 in Mexico calculated from the effective number of reproductions of the infection (Rt) and compare its evolution with that reported by Italy, Spain and the United States of America during the first twenty weeks of evolution of the epidemic. In an analytical cross-sectional design, the total number of cases of COVID-19 in Mexico from February 29 to July 24, 2020 was studied, and compared with sentinel cases calculated from the Rt. A descriptive and comparative analysis of prevalence, cumulative incidence and case fatality was performed to summarize the epidemiological data for Mexico and in relation to information for Italy, Spain, and the United States of North America. In Mexico, until July 24, 2020, there are a total of 390,516 cases of COVID-19 and 43,680 deaths from this disease; with the use of Rt to calculate the correction of cases and unidentified deaths, the figure increases to 3,780,195 cases (p = 0.0002) and 211,469 deaths (p = 0.001). This suggests underreporting in the identification of cases and deaths and is associated with one of the highest case fatality rates in the world for SARS-CoV-2 infection. In Mexico, the sentinel model presents a significant loss of unquantified information. It is necessary to reinforce epidemiological surveillance through a better case detection strategy in our country and continue to apply measures that allow the containment and mitigation of the COVID-19 pandemic.


Herpesvirus saimiri strain 11 immortalizes a restricted marmoset T8 lymphocyte subpopulation in vitro.
Herpesvirus saimiri induces a fatal lymphoproliferative syndrome in a variety of New World primate species. We now show that cell lines derived from PBL of the common marmoset by in vitro-immortalization with H. saimiri strain 11 represent a remarkably restricted lymphocyte population. These cell lines have NK cell function, phenotypically express both suppressor/cytotoxic (T8) and NK cell (NKH1)-associated antigens, and express a T cell receptor. This subpopulation of lymphocytes is a very minor population of cells in the peripheral blood of common marmosets (less than or equal to 3%). The specificity in the interaction between H. saimiri strain 11 and a subpopulation of common marmoset lymphocytes represents an example of a restricted viral lymphotropism and may have important implications for the disease induced by this virus in New World monkeys.


Saxitoxin, a toxic marine natural product that targets a multitude of receptors.
Saxitoxin (STX) was discovered early last century and can contaminate seafood and drinking water, and over time has become an invaluable research tool and an internationally regulated chemical weapon. Among natural products, toxins obtain a unique reputation from their high affinity and selectivity for their target pharmacological receptor, which for STX has long been considered to only be the voltage gated sodium channel. In recent times however, STX has been discovered to also bind to calcium and potassium channels, neuronal nitric oxide synthase, STX metabolizing enzymes and two circulatory fluid proteins, namely a transferrin-like family of proteins and a unique protein found in the blood of pufferfish.


Induction and concurrent paclitaxel/carboplatin every 3 weeks with thoracic radiotherapy in locally advanced non-small-cell lung cancer: an interim report.
The paclitaxel/carboplatin combination has demonstrated promising activity in metastatic non-small-cell lung cancer (NSCLC); therefore, we mounted an exploratory study of these agents with thoracic radiation (TRT) in locally advanced NSCLC. Eligibility stipulated a Karnofsky performance status >or= 70%, weight loss <or= 5%, and primarily stage IIIB or bulky IIIA NSCLC. Induction chemotherapy (CT), 2 cycles of paclitaxel 175-225 mg/m2 over 3 hours and carboplatin (targeted area under the curve [AUC] of 7.5), was administered on days 1 and 22. Granulocyte colony-stimulating factor (G-CSF) 5 microg/kg was given on days 2-15 and 23-36 to all patients; half were randomized to priming G-CSF every day x 5 prior to day 1 of induction therapy. On day 43, TRT (60-63 Gy/30-34 fx) was initiated. At dose level 1, only Fox Chase Cancer Center patients received carboplatin (initial target AUC 3.75) and paclitaxel (67.5 mg/m2 over 3 hours) days 43 and 64. In the absence of dose-limiting toxicity, phase I dose escalation in 3-patient cohorts was scheduled to proceed to a maximum carboplatin AUC 7.5 and paclitaxel dose of 210 mg/m2. To date, 53 patients have received induction therapy; 4 are too early to evaluate. The portion of the study evaluating G-CSF priming revealed no myeloprotective effect, likely due to a lack of myelosuppressive toxicity with the conventionally dosed cohort. Twenty-two patients have received concurrent TRT/CT. In sequential cohorts, the chemotherapy doses on days 43 and 64 have been escalated (to paclitaxel 175 mg/m2 and carboplatin AUC 5) with 1 episode each of grade 4 granulocytopenia and grade 3 anemia. The occurrence of grade >or= 2 esophagitis has corresponded to length (> 16 cm) of esophagus in the radiation treatment field (Fisher's exact test, P = 0.006). The partial response rate to induction therapy was 40% and to the combined modality therapy was 60%. The median survival for all 49 patients is 15.3 months, with a median disease-free survival (DFS) of 7.8 months. In the subset of 22 patients treated on the phase I portion of the study, the median survival and DFS were 18.5 months and 13.5 months, respectively. Induction therapy with paclitaxel and carboplatin followed by concurrent chemoradiotherapy with the same agents is an active and well-tolerated treatment approach in locally advanced NSCLC. To date, paclitaxel 175 mg/m2 plus carboplatin AUC 5 administered at 3-week intervals for 2 cycles is safe in combination with TRT.


Functional polymorphism in the GPR55 gene is associated with anorexia nervosa.
Endocannabinoids, anandamide, and 2-arachidonoyl glycerol are involved in food intake and appetite. Although anandamide is now thought to be a ligand for vanilloid receptor, receptors that are targets of anandamide could play a similar role in eating behaviors and related disorders. This study therefore focused on the receptor, which is called G-protein-coupled receptor 55 (GPR55) that had recently been reported to have binding affinity for endocannabinoids. Functional analysis of the sole missense polymorphism, rs3749073 (Gly195Val) in the GPR55 gene was performed by detecting the phosphorylation level of extracellular signal-regulated kinase (ERK) in Chinese-Hamster-Ovary (CHO) cells engineered to express human GPR55. Val195 type GPR55 appeared to induce less phosphorylated ERK than Gly195 type GPR55 when CHO cells were treated with anandamide and lysophosphatidylinositol (LPI). An association between the functional Gly195Val polymorphism and anorexia nervosa was tested in a female Japanese population comprising 235 patients and 1244 controls. The Val195 allele and homozygote of the Val195 allele were more abundant in the group of patients diagnosed with anorexia nervosa (P = 0.023, Odds ratio = 1.31 (95% Cl = 1.03-1.37), P = 0.0048, OR = 2.41 (95% Cl = 1.34-4.34), respectively). In conclusion, the low-functioning Val195 allele of GPR55 appears to be a risk factor for anorexia nervosa.


Enhancement of Magnetic and Dielectric Properties of Ni0.25Cu0.25Zn0.50Fe2O4 Magnetic Nanoparticles through Non-Thermal Microwave Plasma Treatment for High-Frequency and Energy Storage Applications.
Spinel ferrites are widely investigated for their widespread applications in high-frequency and energy storage devices. This work focuses on enhancing the magnetic and dielectric properties of Ni0.25Cu0.25Zn0.50 ferrite series through non-thermal microwave plasma exposure under low-pressure conditions. A series of Ni0.25Cu0.25Zn0.50 ferrites was produced using a facile sol-gel auto-ignition approach. The post-synthesis plasma treatment was given in a low-pressure chamber by sustaining oxygen plasma with a microwave source. The structural formation of control and plasma-modified ferrites was investigated through X-ray diffraction analysis, which confirmed the formation of the fcc cubical structure of all samples. The plasma treatment did not affect crystallize size but significantly altered the surface porosity. The surface porosity increased after plasma treatment and average crystallite size was measured as about ~49.13 nm. Morphological studies confirmed changes in surface morphology and reduction in particle size on plasma exposure. The saturation magnetization of plasma-exposed ferrites was roughly 65% higher than the control. The saturation magnetization, remnant magnetization, and coercivity of plasma-exposed ferrites were calculated as 74.46 emu/g, 26.35 emu/g, and 1040 Oe, respectively. Dielectric characteristics revealed a better response of plasma-exposed ferrites to electromagnetic waves than control. These findings suggest that the plasma-exposed ferrites are good candidates for constructing high-frequency devices.


The composition of an unusual precursor of 50 S ribosomes in a mutant of Escherichia coli.
Escherichia coli strain 15--28 is a mutant which during exponential growth contains large amounts of a '47S' ribonucleoprotein precursor to 50S ribosomes. The '47S particles' are more sensitive to ribonuclease than are 50S ribosomes. The 23 S RNA of 47S particles may be slightly undermethylated, but cannot be distinguished from the 23S RNA of 50S ribosomes by sedimentation or electrophoresis. Isolated particles have 10--15% less protein than do 50S ribosomes; proteins L16, L28 and L33 are absent. Comparison with precursor particles studied by other workers in wild-type strains of E. coli suggests that the assembly of 50S ribosomes in strain 15--28 is atypical.


Tuning the resonance properties of 2D carbon nanotube networks towards a mechanical resonator.
The capabilities of the mechanical resonator-based nanosensors in detecting ultra-small mass or force shifts have driven a continuing exploration of the palette of nanomaterials for such application purposes. Based on large-scale molecular dynamics simulations, we have assessed the applicability of a new class of carbon nanomaterials for nanoresonator usage, i.e. the single-wall carbon nanotube (SWNT) network. It is found that SWNT networks inherit excellent mechanical properties from the constituent SWNTs, possessing a high natural frequency. However, although a high quality factor is suggested from the simulation results, it is hard to obtain an unambiguous Q-factor due to the existence of vibration modes in addition to the dominant mode. The nonlinearities resulting from these extra vibration modes are found to exist uniformly under various testing conditions including different initial actuations and temperatures. Further testing shows that these modes can be effectively suppressed through the introduction of axial strain, leading to an extremely high quality factor in the order of 10(9) estimated from the SWNT network with 2% tensile strain. Additional studies indicate that the carbon rings connecting the SWNTs can also be used to alter the vibrational properties of the resulting network. This study suggests that the SWNT network can be a good candidate for applications as nanoresonators.


Types of tumors and outcome of treatment of 12 patients with nonmalignant fibrosing tumors in the pediatric hand.
Nonmalignant fibrosing tumors in the pediatric hand or juvenile fibromatoses are uncommon and so may be a challenge to the clinician. We propose a diagnostic and treatment approach to nonmalignant fibrosing tumors of the pediatric hand based on a review of 12 patients who presented with 16 distinct hand lesions. We performed a retrospective 7-year chart review of 12 pediatric patients all with nonmalignant fibrosing conditions of the hand. All patients were operated on by a single surgeon (D.N.) and all samples were reviewed by a single pathologist (E.P.). Twenty-eight surgical procedures were performed on 12 patients. Lesions were classified by location (7 palmar, 9 dorsal) as well as clinicopathologic characteristics. It is imperative to have a broad differential when entertaining the diagnosis of juvenile fibromatosis. Most important, a diagnosis of true cancer must be ruled out. Other mimickers of this process (eg, juvenile rheumatoid arthritis) must also be considered. Most evaluations begin with magnetic resonance imaging and biopsy but a careful history is, as always, a key part of the evaluation. Some lesions may be observed once a diagnosis has been made. When surgical excision is indicated, wide resection is necessary. This may then require flap reconstruction with tendon and joint repair.


Grief and bereavement: what psychiatrists need to know.
THIS REVIEW COVERS FOUR AREAS OF CLINICAL IMPORTANCE TO PRACTICING PSYCHIATRISTS: a) symptoms and course of uncomplicated (normal) grief; b) differential diagnosis, clinical characteristics and treatment of complicated grief; c) differential diagnosis, clinical characteristics and treatment of grief-related major depression; and d) psychiatrists' reactions to patient suicides. Psychiatrists often are ill prepared to identify complicated grief and grief-related major depression, and may not always be trained to identify or provide the most appropriate course of treatment. Both conditions overlap with symptoms found in ordinary, uncomplicated grief, and often are written off as "normal" with the faulty assumption that time, strength of character and the natural support system will heal. While uncomplicated grief may be extremely painful, disruptive and consuming, it is usually tolerable and self-limited and does not require formal treatment. However, both complicated grief and grief-related major depression can be persistent and gravely disabling, can dramatically interfere with function and quality of life, and may even be life threatening in the absence of treatment; and both usually respond to targeted psychiatric interventions. In addition, patient suicide has been reported as one of the most frequent and stressful crises experienced by health providers, and psychiatrists are not immune to complicated grief or grief-related depression when they, themselves, become survivors. Thus, it is essential for psychiatrists to recognize their own vulnerabilities to the personal assaults that often accompany such losses, not only for their own mental health and well-being, but also to provide the most sensitive and enlightened care to their patients.


Validation of Endurance Model for Manual Tasks.
Physical fatigue in the workplace can lead to work-related musculoskeletal disorders (WMSDs), especially in occupations that require repetitive, mid-air movements, such as manufacturing and assembly tasks in industry settings. The current paper endeavors to validate an existing torque-based fatigue prediction model for lifting tasks. The model uses anthropometrics and the maximum torque of the individual to predict the time to fatigue. Twelve participants took part in the study which measured body composition parameters and the maximum force produced by the shoulder joint in flexion, followed by three lifting tasks for the shoulder in flexion, including isometric and dynamic tasks with one and two hands. Inertial measurements units (IMUs) were worn by participants to determine the torque at each instant to calculate the endurance time and CE, while a self-subjective questionnaire was utilized to assess physical exertion, the Borg Rate of Perceived Exertion (RPE) scale. The model was effective for static and two-handed tasks and produced errors in the range of [28.62 49.21] for the last task completed, indicating the previous workloads affect the endurance time, even though the individual perceives they are fully rested. The model was not effective for the one-handed dynamic task and differences were observed between males and females, which will be the focus of future work.An individualized, torque-based fatigue prediction model, such as the model presented, can be used to design worker-specific target levels and workloads, take inter and intra individual differences into account, and put fatigue mitigating interventions into place before fatigue occurs; resulting in potentially preventing WMSDs, aiding in worker wellbeing and benefitting the quality and efficiency of the work output.Clinical Relevance- This research provides the basis for an individualized, torque-based approach to the prediction of fatigue at the shoulder joint which can be used to assign worker tasks and rest breaks, design worker specific targets and reduce the prevalence of work-related musculoskeletal disorders in occupational settings.


Resurgence of human metapneumovirus infection and influenza after three seasons of inactivity in the post-COVID-19 era in Hokkaido, Japan, 2022-2023.
Following the coronavirus disease 2019 (COVID-19) outbreak in February 2020, incidences of various infectious diseases decreased notably in Hokkaido Prefecture, Japan. However, Japan began gradually easing COVID-19 infection control measures in 2022. Here, we conducted a survey of children hospitalized with human metapneumovirus (hMPV), influenza A and B, and respiratory syncytial virus infections in 18 hospitals across Hokkaido Prefecture, Japan, spanning from July 2019 to June 2023. From March 2020 to June 2022 (28 months), only 13 patients were hospitalized with hMPV, and two patients had influenza A. However, in October to November 2022, there was a re-emergence of hMPV infections, with a maximum of 27 hospitalizations per week. From July 2022 to June 2023 (12 months), the number of hMPV-related hospitalizations dramatically increased to 317 patients, with the majority aged 3-6 years (38.2%, [121/317]). Influenza A also showed an increase from December 2022, with a peak of 13 hospitalizations per week in March 2023, considerably fewer than the pre-COVID-19 outbreak in December 2019, when rates reached 45 hospitalizations per week. These findings suggest the possibility of observing more resurgences in infectious diseases in Japan after 2023 if infection control measures continue to be relaxed. Caution is needed in managing potential outbreaks.


Toward tailored functional design of multi-walled carbon nanotubes (MWNTs): electrochemical and antimicrobial activity enhancement via oxidation and selective reduction.
Multiwalled carbon nanotubes (MWNTs) are utilized in a number of sectors as a result of their favorable electronic properties. In addition, MWNT antimicrobial properties can be exploited or considered a potential liability depending on their intended application and handling. The ability to tailor electrochemical and antimicrobial properties using economical and conventional treatment processes introduces the potential to significantly enhance product performance. Oxygen functional groups are known to influence several MWNT properties, including redox activity. Here, MWNTs were functionalized with oxygen groups using standard acid treatments followed by selective reduction via annealing. Chemical derivatization coupled to X-ray photoelectron spectroscopy was utilized to quantify specific surface oxygen group concentration after variable treatment conditions, which were then correlated to observed trends in electrochemical and antimicrobial activities. These activities were evaluated as the potential for MWNTs to participate in the oxygen reduction reaction and to have the ability to promote the oxidation of glutathione. The compiled results strongly suggest that the reduction of surface carboxyl groups and the redox activity of carbonyl groups promote enhanced MWNT reactivity and elucidate the opportunity to design functional MWNTs for enhanced performance in their intended electrochemical or antimicrobial application.


Definitive chemoradiotherapy for clinical T4b esophageal cancer - Treatment outcomes, failure patterns, and prognostic factors.
The management of cT4b thoracic esophageal cancer (EC) is challenging. The optimal treatment remains unclear, and prospective or large-scale retrospective reports on treatment outcomes are lacking. The present study was conducted to investigate the treatment outcomes, failure patterns, treatment responses, and prognostic factors focusing on cT4b thoracic EC treated by definitive concurrent chemoradiotherapy (dCRT). A retrospective review of cT4b thoracic EC patients treated with curative intent dCRT at our institution between 2009 and 2017 was conducted. Survival analysis was calculated using the Kaplan-Meier method, and prognostic factors were examined by the Cox proportional hazards model. A total of 95 cT4b EC patients were included, and the median survival was 11.4 months. The 1-year, 3-year, and 5-year survival rates were 49.4%, 22.2%, and 19.0%, respectively. Forty-six patients (48.4%) experienced locoregional failure, 3 patients (3.2%) developed distant metastasis, and 11 patients had synchronous locoregional and distant failure. The corresponding 1-year, 3-year, and 5-year locoregional failure rates were 62.6%, 74.5%, and 79.2%, respectively. The treatment response rate was 76.9%, and clinical complete response was achieved in 25.3% of patients. Multivariable analysis revealed that age ≤ 65 (p = 0.003), pre-dCRT body mass index (BMI) > 21 (p < 0.001), clinical N stage 0-1 (p = 0.014), and tumor length ≤ 6 cm (p = 0.026) were independent prognosticators for better survival. Our study revealed that long-term survival is achievable for cT4b EC patients treated by dCRT, with a 3-year survival rate of more than 20%. Locoregional recurrence was the most common failure pattern. Age, BMI, N stage, and tumor length were significant prognosticators for survival in this group of patients.


MOZ-mediated repression of p16(INK) (4) (a) is critical for the self-renewal of neural and hematopoietic stem cells.
Although inhibition of p16(INK4a) expression is critical to preserve the proliferative capacity of stem cells, the molecular mechanisms responsible for silencing p16(INK4a) expression remain poorly characterized. Here, we show that the histone acetyltransferase (HAT) monocytic leukemia zinc finger protein (MOZ) controls the proliferation of both hematopoietic and neural stem cells by modulating the transcriptional repression of p16(INK4a) . In the absence of the HAT activity of MOZ, expression of p16(INK4a) is upregulated in progenitor and stem cells, inducing an early entrance into replicative senescence. Genetic deletion of p16(INK4a) reverses the proliferative defect in both Moz(HAT) (-) (/) (-) hematopoietic and neural progenitors. Our results suggest a critical requirement for MOZ HAT activity to silence p16(INK4a) expression and to protect stem cells from early entrance into replicative senescence.


Impact of Frailty on Cardiovascular Disease (and the Other Way Around).
Cardiovascular disesase has been identified as the most frequent cause of death, while frailty has been identified as one of geriatric giants characterized by decreased physiological reserves and increased vulnerability. Despite of aggressive treatment for cardiovascular diseases such as invasive methods,frail patients who undergo these procedures tend to experience undesirable effects compared to non frail patients. As the population of elderly patiens worldwide is growing larger, these issues lead to major health problems that we have to overcome. Association between frailty and cardiovascular disease is still debatable. Cardiovascular disease accelerates frailty. On the other hand, frail patients have higher risk of cardiac mortality and major cardiac events due to their complex health status. However, by doing good risk prediction and assessment, interventional treatment can be performed safely in selected older patients. To date, only a few studies have been conducted to investigate relationship between these two major health problems in elderly. Therefore, in this edition we highlight a study which investigate association between frailty and major adverse cardiac events in patients who underwent invasive intervention. Further researches are still needed to establish evidences between these two geriatric major health problems.


Weakly supervised natural language processing for assessing patient-centered outcome following prostate cancer treatment.
The population-based assessment of patient-centered outcomes (PCOs) has been limited by the efficient and accurate collection of these data. Natural language processing (NLP) pipelines can determine whether a clinical note within an electronic medical record contains evidence on these data. We present and demonstrate the accuracy of an NLP pipeline that targets to assess the presence, absence, or risk discussion of two important PCOs following prostate cancer treatment: urinary incontinence (UI) and bowel dysfunction (BD). We propose a weakly supervised NLP approach which annotates electronic medical record clinical notes without requiring manual chart review. A weighted function of neural word embedding was used to create a sentence-level vector representation of relevant expressions extracted from the clinical notes. Sentence vectors were used as input for a multinomial logistic model, with output being either presence, absence or risk discussion of UI/BD. The classifier was trained based on automated sentence annotation depending only on domain-specific dictionaries (weak supervision). The model achieved an average F1 score of 0.86 for the sentence-level, three-tier classification task (presence/absence/risk) in both UI and BD. The model also outperformed a pre-existing rule-based model for note-level annotation of UI with significant margin. We demonstrate a machine learning method to categorize clinical notes based on important PCOs that trains a classifier on sentence vector representations labeled with a domain-specific dictionary, which eliminates the need for manual engineering of linguistic rules or manual chart review for extracting the PCOs. The weakly supervised NLP pipeline showed promising sensitivity and specificity for identifying important PCOs in unstructured clinical text notes compared to rule-based algorithms.


Endothelial, inflammatory, coagulation, metabolic effects and safety of etravirine in HIV-uninfected volunteers.
The innate proatherosclerotic properties of non-nucleoside reverse transcriptase inhibitors have not previously been examined. Therefore, we performed a pilot study of etravirine (ETR) in healthy volunteers over 28 days. This investigation also allowed us to evaluate the safety of ETR over a period commonly used for HIV postexposure prophylaxis. ETR 200 mg twice daily was given to 28 healthy HIV-uninfected volunteers over 28 days. Flow-mediated dilation (FMD) of the brachial artery and circulating markers of inflammation, coagulation, and metabolism were measured at entry and at day 28. These circulating markers were also measured at day 35. Of the initial 28 subjects, 23 completed both entry and day 28 procedures. Two subjects were discontinued due to development of rash. No other major toxicities developed. The change in FMD over 28 days was minimal and not significant (0.03 [-3.21, 0.97] %; p=0.36). The post hoc estimated detectable absolute change in FMD with the 23 subjects in our study was 2.26%, which is an effect size that has been associated with future cardiovascular event rates in the general population; thus our study had sufficient power to find clinically relevant changes in FMD. In addition, there were no significant changes in any of the circulating markers from entry to day 28 or from day 28 to day 35. ETR did not demonstrate any innate proatherosclerotic properties over 28 days in these HIV-uninfected volunteers. ETR was generally well tolerated. Larger studies are warranted to confirm that ETR can be used safely as part of HIV postexposure prophylaxis regimens.


The catalytic subunit of DNA-dependent protein kinase regulates proliferation, telomere length, and genomic stability in human somatic cells.
The DNA-dependent protein kinase (DNA-PK) complex is a serine/threonine protein kinase comprised of a 469-kDa catalytic subunit (DNA-PK(cs)) and the DNA binding regulatory heterodimeric (Ku70/Ku86) complex Ku. DNA-PK functions in the nonhomologous end-joining pathway for the repair of DNA double-stranded breaks (DSBs) introduced by either exogenous DNA damage or endogenous processes, such as lymphoid V(D)J recombination. Not surprisingly, mutations in Ku70, Ku86, or DNA-PK(cs) result in animals that are sensitive to agents that cause DSBs and that are also immune deficient. While these phenotypes have been validated in several model systems, an extension of them to humans has been missing due to the lack of patients with mutations in any one of the three DNA-PK subunits. The worldwide lack of patients suggests that during mammalian evolution this complex has become uniquely essential in primates. This hypothesis was substantiated by the demonstration that functional inactivation of either Ku70 or Ku86 in human somatic cell lines is lethal. Here we report on the functional inactivation of DNA-PK(cs) in human somatic cells. Surprisingly, DNA-PK(cs) does not appear to be essential, although the cell line lacking this gene has profound proliferation and genomic stability deficits not observed for other mammalian systems.


[Effects of Combined Stress of Polyethylene and Sulfamethazine on Seed Germination, Seedling Growth, and Physiological Characteristics of Soybean].
The combined pollution of antibiotics adsorption by microplastics has become inevitable in soil ecosystems; moreover, the plant biological effects under combined stress remain unclear. This study used soybean variety Jindou 21 as the material and conducted seed germination test and soil-potted seedling experiment to study the effects of different single and combined treatments of polyethylene (PE) and sulfamethazine (SMZ) on seed germination, seedling growth, photosynthetic parameters, chlorophyll fluorescence parameters, and nitrogen metabolism. The results showed that single PE treatment at low levels promoted soybean seed germination and seedling growth physiology; however, inhibited them at a high level. A lower-level PE treatment[10 mg·L-1 (or mg·kg-1)] could promote soybean seed germination, seedling growth, photosynthesis, and nitrogen metabolism, whereas a higher level PE treatment[100 mg·L-1 and 200 mg·L-1 (or mg·kg-1)] had significant inhibition. The single SMZ treatment had different degrees of inhibition on soybean seed germination and seedling growth physiology, and the inhibition degree increased with the increase in SMZ treatment level. Under the different levels of combined treatments of PE and SMZ, adding the lower level PE treatment could alleviate the inhibition of the single SMZ treatment on soybean, with 10 mg·L-1(or mg·kg-1) PE+1 mg·L-1(or mg·kg-1) SMZ treatment having the best comprehensive mitigation effect, which could increase soybean seed germination potential, germination rate, germination index, vigor index, plant height, root length, shoot and root fresh weight, Pn, Gs, Tr, chlorophyll contents, Fv/Fm, ΦPSⅡ, ETR, qP, and key enzyme activities for nitrogen metabolism such as NR and decrease the average germination time, Ci, NPQ, and NO3--N and NH4+-N contents compared with those in the single SMZ treatment. Adding the higher level PE treatment enhanced the inhibition of SMZ on soybean, and the inhibition degree increased with the increase in SMZ treatment level, in which 200 mg·L-1(or mg·kg-1) PE+50 mg·L-1(or mg·kg-1) SMZ treatment yielded the greatest inhibition. In summary, the lower level PE treatment could alleviate the inhibition of SMZ on soybean seeds and seedlings to a certain extent; however, the higher level PE treatment could produce a synergistic effect with SMZ, thus aggravating the toxic effect of the single stress treatment.


Effects of bacterial pollution caused by a strong typhoon event and the restoration of a recreational beach: Transitions of fecal bacterial counts and bacterial flora in beach sand.
To determine the effects of bacteria pollution associated with a strong typhoon event and to assess the restoration of the normal bacterial flora, we used conventional filtration methods and nextgeneration sequencing of 16S rRNA genes to analyze the transition of fecal and total bacterial counts in water and core sand samples collected from a recreational beach. Immediately after the typhoon event, Escherichia coli counts increased to 82 CFU/100 g in the surface beach sand. E. coli was detected through the surface to sand 85-cm deep at the land side point (10-m land side from the high-water line). However, E. coli disappeared within a month from the land side point. The composition of the bacterial flora in the beach sand at the land point was directly influenced by the typhoon event. Pseudomonas was the most prevalent genus throughout the sand layers (0-102-cm deep) during the typhoon event. After 3 months, the population of Pseudomonas significantly decreased, and the predominant genus in the surface layer was Kaistobacter, although Pseudomonas was the major genus in the 17- to 85-cm layer. When the beach conditions stabilized, the number of pollutant Pseudomonas among the 10 most abundant genera decreased to lower than the limit of detection. The bacterial population of the sand was subsequently restored to the most populous pre-event orders at the land point. A land-side beach, where users directly contact the sand, was significantly affected by bacterial pollution caused by a strong typhoon event. We show here that the normal bacterial flora of the surface sand was restored within 1 month.


Targeting hypertension with a new adenosine triphosphate-sensitive potassium channel opener iptakalim.
Hypertension is the most common cardiovascular disease. The discovery of the antihypertensive action of adenosine triphosphate-sensitive potassium (K(ATP)) channel openers was a significant advance in the treatment of hypertension. Iptakalim is a novel K(ATP) channel opener with a unique chemical structure that differs from other K(ATP) openers. Among the 3 different subtypes of K(ATP) channels heterologously expressed in human embryonic kidney cells and Xenopus oocytes, iptakalim exhibits significant selectivity for SUR2B/Kir6.1 channels, mild effects on SUR2A/Kir6.2 channels, and fails to open SUR1/Kir6.2 channels. Iptakalim is a more potent activator of the SUR2B/Kir6.1 subtype of K(ATP) channels than diazoxide and pinacidil, the 2 most commonly studied K(ATP) channel openers. Iptakalim selectively produces arteriolar vasodilation with essentially no effect on the capacitance vessels. It can preferentially relax arterioles and small arteries, without affecting large arteries. Furthermore, iptakalim strongly lowers the blood pressure of hypertensive rodents and humans but has little effect on normotensive rodents and humans. Selective antihypertensive action is not observed with pinacidil or diazoxide and may be due to the high selectivity of iptakalim for the SUR2B/Kir6.1 subtype of K(ATP) channels, as well as its selective relaxation of resistance vessels. In pulmonary arterial smooth muscle cells, iptakalim inhibits the increase of cytoplasmic free Ca2+ concentration, as well as cell proliferation induced by endothelin-1. Furthermore, iptakalim has exerted protective effects against hypertensive damage to target organs in rats and improves endothelial dysfunction associated with cardiovascular diseases by selective activation of the SUR2B/Kir6.1 subtype of K(ATP) channels expressed in the endothelium. Clinical trials of iptakalim in the treatment of mild-moderate hypertension have been completed in China. In additional to strong antihypertensive efficacy, iptakalim seems to have a favorable safety and tolerability profile. Iptakalim is a promising new generation antihypertensive drug.


Microsphere-assisted phase-shifting profilometry.
In the present work, we have investigated the combination of a superresolution microsphere-assisted 2D imaging technique with low-coherence phase-shifting interference microscopy. The imaging performance of this technique is studied by numerical simulation in terms of the magnification and the lateral resolution as a function of the geometrical and optical parameters. The results of simulations are compared with the experimental measurements of reference gratings using a Linnik interference configuration. Additional measurements are also shown on nanostructures. An improvement by a factor of 4.7 in the lateral resolution is demonstrated in air, thus giving a more isotropic nanometric resolution for full-field surface profilometry in the far field.


[Acoustic and mechanical properties of tympanic membrane transplants].
The human tympanic membrane has reasonably good sound transmission properties and withstands high static pressure loads. Destruction of the tympanic membrane resulting from middle ear diseases or trauma may be repaired by different types of grafts. Middle ear surgery mostly uses autologous temporal fascia, cartilage, or cartilage perichondrium transplants which differ in their acoustical characteristics and mechanical strength. We have investigated the acoustical and mechanical properties of these materials and compared them with human tympanic membranes by constructing an ear canal-tympanic membrane model. Fresh human tympanic membrane, fascia, perichondrium, and cartilage preparations were exposed to static pressures up to 4 kPa and white noise sound pressure levels of 70 dB. The vibrational amplitudes and displacements due to static pressure were measured by laser Doppler vibrometry. The temporal fascia and perichondrium show similar amplitude frequency responses compared to the tympanic membrane for dynamic excitation. The displacement of these materials at static pressures above 4 kPa indicates a higher compliance than the tympanic membrane. The acoustical and mechanical properties of cartilage transplants are determined by the thickness of the slices. Thin cartilage slices are less stable although their frequency response is comparable to the intact tympanic membrane. Layer thickness above 500 microns result in a decrease of vibration amplitudes. Cartilage is an excellent transplant material which provides a better prognosis than soft materials in cases of ventilation disorders with long-term middle ear pressure problems. Large cartilage slice transplants should not exceed layer thickness of 500 microns in order to minimize transmission loss.


Phospholipid ether analogs for the detection of colorectal tumors.
The treatment of localized colorectal cancer (CRC) depends on resection of the primary tumor with adequate margins and sufficient lymph node sampling. A novel imaging agent that accumulates in CRCs and the associated lymph nodes is needed. Cellectar Biosciences has developed a phospholipid ether analog platform that is both diagnostic and therapeutic. CLR1502 is a near-infrared fluorescent molecule, whereas 124/131I-CLR1404 is under clinical investigation as a PET tracer/therapeutic agent imaged by SPECT. We investigated the use of CLR1502 for the detection of intestinal cancers in a murine model and 131I-CLR1404 in a patient with metastatic CRC. Mice that develop multiple intestinal tumors ranging from adenomas to locally advanced adenocarcinomas were utilized. After 96 hours post CLR1502 injection, the intestinal tumors were analyzed using a Spectrum IVIS (Perkin Elmer) and a Fluobeam (Fluoptics). The intensity of the fluorescent signal was correlated with the histological characteristics for each tumor. Colon adenocarcinomas demonstrated increased accumulation of CLR1502 compared to non-invasive lesions (total radiant efficiency: 1.76×10(10) vs 3.27×10(9) respectively, p = 0.006). Metastatic mesenteric tumors and uninvolved lymph nodes were detected with CLR1502. In addition, SPECT imaging with 131I-CLR1404 was performed as part of a clinical trial in patients with advanced solid tumors. 131I-CLR1404 was shown to accumulate in metastatic tumors in a patient with colorectal adenocarcinoma. Together, these compounds might enhance our ability to properly resect CRCs through better localization of the primary tumor and improved lymph node identification as well as detect distant disease.


Discriminative stimulus properties of caffeine in the rat: noradrenergic mediation.
The stimulus properties of caffeine were studied in separate groups of rats trained to discriminate between i.p. injections of saline and either 10 or 30 mg/kg of caffeine in a discrete-trial avoidance paradigm. Stimulus control of behavior (i.e., reliable completion of at least 18 of 20 trials on the appropriate choice lever after injection of saline or caffeine) was established in an average of 50 to 52 sessions. Novel drugs were tested over a range of doses for generalization to one (10 mg/kg) or both doses of caffeine. The methylxanthine derivatives, theophylline, theobromine, 1,7-dimethylxanthine, 3-isobutyl-l-methylxanthine, 8-phenyltheophylline and 8-chlorotheophylline, were generalized to caffeine partially or not at all. Of the nonxanthine drugs, apomorphine, clonidine and picrotoxin occasioned responding only on the saline-appropriate choice lever, d-amphetamine and ephedrine generalized partially, and cocaine and methylphenidate generalized with caffeine completely, as did 2-(2-chloro-5-trifluoromethylphenylimino)imidazolidine an alpha-1 adrenergic receptor agonist. The discriminative effects of 10 mg/kg of caffeine were blocked dose-dependently and completely by alpha adrenergic receptor blocking drugs (phentolamine, prazosin and yohimbine) and were blocked partially by propranolol and by drugs having behavioral depressant properties (diazepam, pentobarbital and the adenosine analogs, R-(-)-N6-(2-phenylisopropyl)adenosine, cyclohexyladenosine, 2-chloroadenosine). The blockade by phentolamine could be surmounted by increasing the dose of caffeine, the partial blockade by diazepam and 2-chloroadenosine could not. Alpha adrenergic receptor blocking drugs also antagonized the caffeine-like discriminative effects of methylphenidate and 2-(2-chloro-5-trifluoromethylphenylimino)imidazolidine. The discriminative stimulus effects of caffeine in the rat appear to be mediated in part by alpha adrenergic mechanisms.


Development and validation of a core outcome measure for palliative care: the palliative care outcome scale. Palliative Care Core Audit Project Advisory Group.
To develop an outcome measure for patients with advanced cancer and their families which would cover more than either physical symptoms or quality of life related questions. To validate the measure in various specialist and non-specialist palliative care settings throughout the UK. A systematic literature review of measures appropriate for use in palliative care settings was conducted. In conjunction with a multidisciplinary project advisory group, questions were chosen for inclusion into the scale based on whether they measured aspects of physical, psychological, or spiritual domains pertinent to palliative care, and whether similar items had shown to be valid as part of another measure. A staff completed version was developed to facilitate data collection on all patients throughout their care, and a patient completed version was designed to enable the patient to contribute to the assessment of their outcomes when possible. A full validation study was conducted to evaluate construct validity, internal consistency, responsiveness to change over time, and test-retest reliability. Assessments were timed. Eight centres in England and Scotland providing palliative care, including inpatient care, outpatient care, day care, home care, and primary care. A total of 450 patients entered care during the study period. Staff collected data routinely on patients in care long enough to be assessed (n = 337). Of these, 262 were eligible for patient participation; 148 (33%) went on to complete a questionnaire. The Palliative Care Outcome Scale (POS), the European Organisation for Research on Cancer Treatment, and the Support Team Assessment Schedule. The POS consists of two almost identical measures, one of which is completed by staff, the other by patients. Agreement between staff and patient ratings was found to be acceptable for eight out of 10 items at the first assessment. The measure demonstrated construct validity (Spearman rho = 0.43 to 0.80). Test/re-test reliability was acceptable for seven items. Internal consistency was good (Cronbach's alpha = 0.65 (patients), 0.70 (staff)). Change over time was shown, but did not reach statistical significance. The questionnaire did not take more than 10 minutes to complete by staff or patients. The POS has acceptable validity and reliability. It can be used to assess prospectively palliative care for patients with advanced cancer.


Toward a model of microsaccade generation: the case of microsaccadic inhibition.
Microsaccades are one component of the small eye movements that constitute fixation. Their implementation in the oculomotor system is unknown. To better understand the physiological and mechanistic processes underlying microsaccade generation, we studied microsaccadic inhibition, a transient drop of microsaccade rate, in response to irrelevant visual and auditory stimuli. Quantitative descriptions of the time course and strength of inhibition revealed a strong dependence of microsaccadic inhibition on stimulus characteristics. In Experiment 1, microsaccadic inhibition occurred sooner after auditory than after visual stimuli and after luminance-contrast than after color-contrast visual stimuli. Moreover, microsaccade amplitude strongly decreased during microsaccadic inhibition. In Experiment 2, the latency of microsaccadic inhibition increased with decreasing luminance contrast. We develop a conceptual model of microsaccade generation in which microsaccades result from fixation-related activity in a motor map coding for both fixation and saccades. In this map, fixation is represented at the central site. Saccades are generated by activity in the periphery, their amplitude increasing with eccentricity. The activity at the central, fixation-related site of the map predicts the rate of microsaccades as well as their amplitude and direction distributions. This model represents a framework for understanding the dynamics of microsaccade behavior in a broad range of tasks.


Federated Learning in Medical Imaging: Part I: Toward Multicentral Health Care Ecosystems.
With recent developments in medical imaging facilities, extensive medical imaging data are produced every day. This increasing amount of data provides an opportunity for researchers to develop data-driven methods and deliver better health care. However, data-driven models require a large amount of data to be adequately trained. Furthermore, there is always a limited amount of data available in each data center. Hence, deep learning models trained on local data centers might not reach their total performance capacity. One solution could be to accumulate all data from different centers into one center. However, data privacy regulations do not allow medical institutions to easily combine their data, and this becomes increasingly difficult when institutions from multiple countries are involved. Another solution is to use privacy-preserving algorithms, which can make use of all the data available in multiple centers while keeping the sensitive data private. Federated learning (FL) is such a mechanism that enables deploying large-scale machine learning models trained on different data centers without sharing sensitive data. In FL, instead of transferring data, a general model is trained on local data sets and transferred between data centers. FL has been identified as a promising field of research, with extensive possible uses in medical research and practice. This article introduces FL, with a comprehensive look into its concepts and recent research trends in medical imaging.


Discrimination of knee osteoarthritis patients from asymptomatic individuals based on pain sensitivity and knee vibroarthrographic recordings.
Recording of knee vibroarthrographic (VAG) activity during activities of daily living (ADL) can contribute to diagnose knee osteoarthritis (KOA). However, classifying KOA patients based on knee VAG during ADL has been an elusive problem not related to knee pain. Therefore, the aims of this study was to classify KOA patients based on (1) VAG during ADL and (2) knee pain sensitivity and then compare their results. The experimental procedure consisted of the recording of VAG signals during four ADLs (over-ground gait, stairs descent, stairs ascent and sit-to-stand) from eight patellar and peri-patellar locations in 20 KOA and 20 asymptomatic participants. Pressure pain thresholds (PPT) were obtained from eight locations around the knee joint to quantify pain sensitivity. A random forest classifier was utilized to identify KOA patients based on VAG signal features and PPTs. The most important features contributing to the classification accuracy were determined. The KOA patients participated in a second identical experimental session to examine the day-to-day reproducibility. The participants were classified with accuracy of 90%, 70%, 64% and 82% during over-ground gait, stairs descent, stairs ascent and sit to stand, respectively. However, the accuracy of the classifier was reduced by about 10%-25% due to a systematic bias in the extracted features across days. Features of the VAG signals in time and frequency domains as well as nonlinear features were found importantly contributing towards the classification accuracy. The VAG features extracted from the lateral side of the knee was found to be more informative than other locations. The classification based on PPT reached 77%. Medial and proximal knee PPT points contributed to the classification accuracy. This study showed that using multichannel VAG signals to identify KOA patients allows better accuracy than the use of PPTs. However, VAG setup must be standardized to avoid day-to-day bias.


A comparative study on heuristic algorithms for generating fuzzy decision trees.
Fuzzy decision tree induction is an important way of learning from examples with fuzzy representation. Since the construction of optimal fuzzy decision tree is NP-hard, the research on heuristic algorithms is necessary. In this paper, three heuristic algorithms for generating fuzzy decision trees are analyzed and compared. One of them is proposed by the authors. The comparisons are twofold. One is the analytic comparison based on expanded attribute selection and reasoning mechanism; the other is the experimental comparison based on the size of generated trees and learning accuracy. The purpose of this study is to explore comparative strengths and weaknesses of the three heuristics and to show some useful guidelines on how to choose an appropriate heuristic for a particular problem.


[Analysis of the formation of complex conditioned reflex systems].
A method is proposed of separating processes of current learning and long-term memory by a qualitative and quantitative analysis of erroneous movements performed by the animals during elaboration of one system of reflexes. The dynamics of changes in the number of some of the animal's movements in the process of learning was of a simple exponential nature and reflected the acquisition of new information. The dynamics of changes in the number of other movements was of a more complicated nature. They were classified as searching movements. The number of such movements which in the process of learning prove to be correct, at first decreases, and then increases. The number of searching movements which prove to be wrong, at first increases and then decreases. Analysis of dynamics of changes in the number of searching movements permits to determine the animal's appeal to long-term memory.


Implications of exercise training in mtDNA defects--use it or lose it?
Whether regular exercise is beneficial or should be avoided is a question currently unsettled in patients with heteroplasmic mitochondrial DNA (mtDNA) disorders of skeletal muscle. Deleterious effects of habitual physical inactivity superimposed upon impaired mitochondrial oxidative phosphorylation may contribute to varying degrees of exercise intolerance in these patients. Endurance exercise training is widely known to improve exercise capacity in healthy subjects and various chronic-disease patient populations. Although we have shown that beneficial physiological and biochemical responses to training increase exercise tolerance in patients with mtDNA defects, knowledge of the muscle adaptive response to endurance training within the setting of mitochondrial heteroplasmy remains limited. In order to determine advisability of endurance training as therapy, it remains to be established whether potential endurance training-induced increases in mutant mtDNA levels may be offset by increases in absolute wild-type mtDNA levels, and whether chronic inactivity leads to a selective down-regulation of wild-type mtDNA. Resistance training utilizes a different adaptive exercise approach to induce the transfer of normal mitochondrial templates from satellite cells to mature muscle fibers of patients with sporadic mtDNA disorders. The efficacy and safety of this approach needs to be further established. Our current inability to clearly advise patients to "use it or lose it" underscores the immediate urgency of studying the effects of exercise on skeletal muscle of patients with heteroplasmic mtDNA defects.


Social anxiety and insomnia: the mediating role of depressive symptoms.
Anxiety is commonly associated with insomnia. Given that social anxiety disorder is one of the most prevalent anxiety disorders, socially anxious individuals may be particularly vulnerable to insomnia. However, there is currently very little empirical work on this relationship. This study used bivariate correlations to examine whether social anxiety was related to insomnia in an undergraduate sample (n=176) using the Social Interaction Anxiety Scale and the Insomnia Severity Index. Further, we utilized responses from the Beck Depression Inventory to investigate the role of depressive symptoms in the association between social anxiety and insomnia. Hierarchical linear regressions were used to examine the moderational and mediational role of depressive symptoms in the link between social anxiety and insomnia. To increase generalizability to clinical samples, analyses were repeated on a subset of the sample with clinically significant social anxiety symptoms (n=23) compared to a matched control group (n=23). Consistent with expectation, social anxiety was associated with increased insomnia symptoms. Specifically, social anxiety was correlated with sleep dissatisfaction, sleep-related functional impairment, perception of a sleep problem to others, and distress about sleep problems. Importantly, depressive symptoms mediated the relationship between social anxiety and insomnia, thereby at least partially accounting for insomnia among socially anxious individuals. Our data support the contention that social anxiety is associated with insomnia and suggest that depression may play a vital role in this co-occurrence.


Relationship between myocardial 123I-metaiodobenzylguanidine scintigraphic uptake and heart rate variability in patients with syndrome X.
We have recently demonstrated a striking impairment in cardiac uptake of 123I-metaiodobenzylguanidine (MIBG) in most patients with syndrome X. In this study we investigated the relationship between cardiac MIBG defects and cardiac autonomic activity in these patients. MIBG myocardial scintigraphy and time-domain and frequency-domain heart rate variability (HRV) were compared in 11 syndrome X patients and 10 healthy controls. Cardiac MIBG uptake was assessed by the heart/mediastinum ratio and a cardiac MIBG uptake defect score (higher values = lower uptake). The heart/mediastinum ratio was lower (1.71 +/- 0.6 vs 2.19 +/- 0.3, p = 0.03) and MIBG uptake score higher (37.1 +/- 32 vs 4.0 +/- 2.5, p = 0.005) in syndrome X patients, whereas average HRV values did not differ between the two groups. However, while there were no correlations between MIBG uptake and HRV in controls, in syndrome X patients both the heart/mediastinum ratio and MIBG uptake score correlated significantly with two HRV parameters, specific for vagal activity: the square root of the mean squared differences of consecutive RR intervals (r = 0.73, p = 0.01, and r = -0.67, p = 0.02, respectively), and high frequency (r = 0.64, p = 0.03, and r = -0.74, p = 0.009, respectively). CONCLUSIONS; In patients with syndrome X, the impairment in cardiac MIBG uptake was associated with a reduction in HRV indexes mainly reflecting vagal modulation of sinus node, thus suggesting that a predominance of cardiac adrenergic activity may be present in those with abnormal cardiac MIBG scintigraphy.


Lithium ion inhibits nerve growth factor-induced neurite outgrowth and phosphorylation of nerve growth factor-modulated microtubule-associated proteins.
LiCl (2.5-20 mM) reversibly suppressed nerve growth factor (NGF)-induced neurite outgrowth by cultured rat PC 12 pheochromocytoma cells. Similar concentrations of LiCl also reversibly blocked NGF-dependent regeneration of neurites by PC12 cells that had been primed by long-term pre-exposure to NGF and by cultured newborn mouse sympathetic neurons. In contrast, transcription-dependent responses of PC12 cells to NGF such as priming and induction of the NGF-inducible large external glycoprotein, occurred despite the presence of Li+. SDS PAGE analysis of total cellular phosphoproteins (labeled by 2-h exposure to 32P-orthophosphate) from neurite-bearing primed PC12 cells revealed that Li+ reversibly inhibited the phosphorylation of a band of Mr 64,000 that was barely detectable in NGF-untreated PC12 cells. However, Li+ did not appear to affect the labeling of other phosphoproteins in either NGF-primed or untreated PC12 cultures, nor did it affect the rapid increase in phosphorylation of several proteins that occurs when NGF is first added to unprimed cultures. Several criteria indicated that the NGF-inducible phosphoprotein of Mr 64,000 is a microtubule-associated protein (MAP). Of the NGF-inducible phosphorylated MAPs that have been detected in PC12 cells (Mr 64,000, 72,000, 80,000, and 320,000), several (Mr 64,000, 72,000, and 80,000) were found to be substantially less phosphorylated in the presence of Li+. Neither a phorbol ester tumor promotor nor permeant cAMP analogs reversed the inhibitory effects of Li+ on neurite outgrowth or on phosphorylation of the component of Mr 64,000. Microtubules are a major and required constituent of neurites, and MAPs may regulate the assembly and stability of neuritic microtubules. The observation that Li+ selectively inhibits NGF-induced neurite outgrowth and MAP phosphorylation suggests a possible causal relationship between these two events.


Fatal viscerotropic Rocky Mountain spotted fever. Report of a case diagnosed by immunofluorescence.
A case of fatal viscerotropic Rocky Mountain spotted fever with virtual absence of cutaneous lesions was diagnosed at autopsy by specific immunofluorescent demonstration of Rickettsia rickettsii in spleen, kidney, epididymis and skin. The clinical presentation was that of insidious onset of fever, renal failure, hypotension, hyponatremia and obtundation over a 10 day period. The patient had respiratory insufficiency, hypocalcemia, increases in creatinine phosphokinase (CPK), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), lactic dehydrogenase (LDH), alkaline phosphatase, billirubin and serum phosphate, grand mal seizure, myalgia and unremitting shock with death occurring on day 12 of illness. Postmortem examination revealed severe vasculitis with interstitial nephritis and multifocal tubular necrosis, pericholangitis with bile stasis, glial nodules in the brain, multifocal rhabdomyonecrosis, interstitial pneumonitis and mild interstitial myocarditis. Risk factors which this patient shared with other patients with fatal Rocky Mountain spotted fever were failure to recognize a rash, failure to obtain a tick bite history, male sex, black race and age greater than 30 years.


Assessment of the Functioning Levels and Related Factors in Patients with Bipolar Disorder during Remission.
The course of bipolar disorder (BD) is characterized by relapse and remission periods. Although the symptoms show a significant and sometimes almost complete improvement during remission, the patients' functioning levels may be lower compared to the premorbid period. This study aimed to compare the functional levels between patients with BD during remission period and healthy controls and to evaluate the factors related to the functional status of the patients. In this cross-sectional study, functioning levels of the BD-I patients, who were in remission for three months or longer, were compared with those of the healthy controls. Young Mania Rating Scale and Hamilton Depression Rating Scale were used to determine remission status, and Bipolar Disorder Functioning Questionnaire (BDFQ) was used to determine the level of functioning. The study included 165 BD-I patients during remission and 63 healthy controls. The BDFQ scores of the patients including intellectual functioning, sexual functioning, feeling of stigmatization, introversion, relationships with friends, participation in social activities, daily activities and hobbies, and taking initiative were found to be statistically significantly lower than those of the controls. When the functioning comparisons were carried out within the patients considering the drugs they were using, the functioning levels including domestic functioning and introversion domains were found to be significantly impaired in those who use at least one antipsychotic in addition to the mood stabilizers than in those who use only mood stabilizers. In BD, the impairments within multiple functioning domains are observed even during remission periods. Besides targeting remission through pharmacological treatment, psychosocial interventions for functioning are also important in the treatment of these patients.


Preferred Orientation Deposition via Multifunctional Gel Electrolyte with Molecular Anchor Enabling Highly Reversible Zn Anode.
The high activity of water molecules results in a series of awful parasitic reaction, which seriously impede the development of aqueous zinc batteries. Herein, a new gel electrolyte with multiple molecular anchors is designed by employing natural biomaterials from chitosan and chlorophyll derivative. The gel electrolyte firmly anchors water molecules by ternary hydrogen bonding to reduce the activity of water molecules and inhibit hydrogen evolution reaction. Meanwhile, the multipolar charged functional groups realize the gradient induction and redistribution of Zn2+ , which drives oriented Zn (002) plane deposition of Zn2+ and then achieves uniform Zn deposition and dendrite-free anode. As a result, it endows the Zn||Zn cell with over 1700 h stripping/plating processes and a high efficiency of 99.4% for the Zn||Cu cell. In addition, the Zn||V2 O5 full cells also exhibit capacity retention of 81.7% after 600 cycles at 0.5 A g-1 and excellent long-term stability over 1600 cycles at 2 A g-1 , and the flexible pouch cells can provide stable power for light-emitting diodes even after repeated bending. The gel electrolyte strategy provides a reference for reversible zinc anode and flexible wearable devices.


Evidence of Cytolysin A nanopore incorporation in mammalian cells assessed by a graphical user interface.
Technologies capable of assessing cellular metabolites with high precision and temporal resolution are currently limited. Recent developments in the field of nanopore sensors allow the non-stochastic quantification of metabolites, where a nanopore is acting as an electrical transducer for selective substrate binding proteins (SBPs). Here we show that incorporation of the pore-forming toxin Cytolysin A (ClyA) into the plasma membrane of Chinese hamster ovary cells (CHO-K1) results in the appearance of single-channel conductance amenable to multiplexed automated patch-clamp (APC) electrophysiology. In CHO-K1 cells, SBPs modify the ionic current flowing though ClyA nanopores, thus demonstrating its potential for metabolite sensing of living cells. Moreover, we developed a graphical user interface for the analysis of the complex signals resulting from multiplexed APC recordings. This system lays the foundation to bridge the gap between recent advances in the nanopore field (e.g., proteomic and transcriptomic) and potential cellular applications.


A new species of Skrjabingylus Petrov, 1927 (Nematoda: Metastrongyloidea) from the frontal sinuses of the hooded skunk, Mephitis macroura (Mustelidae).
Skrjabingylus santaceciliae n. sp. is described based on specimens from the frontal sinuses of a hooded skunk, Mephitis macroura, collected from the Area de Conservación Guanacaste, Costa Rica. Skrjabingylus santaceciliae n. sp. differs from the other 5 species in the genus in having pointed spicule tips that lack a rounded or lobed formation and by lacking a prominent distal projection at the tail tip. Morphometric comparisons show that S. santaceciliae n. sp. is much smaller than the only other valid species from Mephitis, Skrjabingylus chitwoodorum Hill, 1939. Likewise, morphometric comparisons also distinguish S. santaceciliae n. sp. from other described Skrjabingylus species.


Limiting amino acids for a corn and soybean meal diet in weaned calves less than three months of age.
Holstein bull calves (n = 51) weaned at 6 wk of age were used in four N balance trials for 4 wk (Trials 1 to 3) or for 2 wk (Trial 4) from 8 wk of age to identify limiting amino acids for a corn and soybean meal diet. The calves were trained to maintain reflex closure of the reticular groove throughout the trials. In Trial 1, administration of .111 g of DL-methionine plus .333 g of L-lysine monohydrochloride/kg BW through the reticular groove increased N retention compared with the control that received isonitrogenous L-glutamine, but administration of .333 g L-lysine monohydrochloride/kg BW alone did not increase N retention in Trial 2. In Trial 3, administration of .111 g of DL-methionine/kg BW improved N balance compared with the control, although the improvement was not detected when DL-methionine was restricted to .022 g/kg BW. In Trial 4, administration of the mixture of .111 g of DL-methionine, .333 g of L-lysine monohydrochloride, and .055 g of L-tryptophan/kg BW increased N retention in calves compared with calves that received an isonitrogenous mixture of .111 g of DL-methionine and .274 g of L-glutamine/kg BW, or .111 g of DL-methionine, .055 g of L-tryptophan, and .234 g of L-glutamine/kg BW. The present results suggest that methionine was the first-limiting and that lysine was probably the second-limiting amino acid for the corn and soybean meal diet in weaned calves less than 11 wk of age, although tryptophan may be either co-limiting with lysine or third-limiting.


The Melanocortin System in Atlantic Salmon (Salmo salar L.) and Its Role in Appetite Control.
The melanocortin system is a key neuroendocrine network involved in the control of food intake and energy homeostasis in vertebrates. Within the hypothalamus, the system comprises two main distinct neuronal cell populations that express the neuropeptides proopiomelanocortin (POMC; anorexigenic) or agouti-related protein (AGRP; orexigenic). Both bind to the melanocortin-4 receptor (MC4R) in higher order neurons that control both food intake and energy expenditure. This system is relatively well-conserved among vertebrates. However, in Atlantic salmon (Salmo salar L.), the salmonid-specific fourth round whole-genome duplication led to the presence of several paralog genes which might result in divergent functions of the duplicated genes. In the current study, we report the first comprehensive comparative identification and characterization of Mc4r and extend the knowledge of Pomc and Agrp in appetite control in Atlantic salmon. In silico analysis revealed multiple paralogs for mc4r (a1, a2, b1, and b2) in the Atlantic salmon genome and confirmed the paralogs previously described for pomc (a1, a2, and b) and agrp (1 and 2). All Mc4r paralogs are relatively well-conserved with the human homolog, sharing at least 63% amino acid sequence identity. We analyzed the mRNA expression of mc4r, pomc, and agrp genes in eight brain regions of Atlantic salmon post-smolt under two feeding states: normally fed and fasted for 4 days. The mc4ra2 and b1 mRNAs were predominantly and equally abundant in the hypothalamus and telencephalon, the mc4rb2 in the hypothalamus, and a1 in the telencephalon. All pomc genes were highly expressed in the pituitary, followed by the hypothalamus and saccus vasculosus. The agrp genes showed a completely different expression pattern from each other, with prevalent expression of the agrp1 in the hypothalamus and agrp2 in the telencephalon. Fasting did not induce any significant changes in the mRNA level of mc4r, agrp, or pomc paralogs in the hypothalamus or in other highly expressed regions between fed and fasted states. The identification and wide distribution of multiple paralogs of mc4r, pomc, and agrp in Atlantic salmon brain provide new insights and give rise to new questions of the melanocortin system in the appetite regulation in Atlantic salmon.


Histopathological lesions induced by stroke in the encephalon.
Strokes are conditions with a high degree of morbidity and mortality worldwide. These conditions profoundly affect the quality of life of patients; in addition to physical disabilities, patients present various mental disorders, such as mood disorders, anxiety, depression, behavioral disorders, fatigue, etc. Microscopic lesions of the brain parenchyma explain the clinical symptoms and correlate with the severity of the stroke. Our study consisted of the histopathological (HP) and immunohistochemical analysis of brain fragments, collected from 23 patients, with a clinical and imagistic diagnosis of stroke, who died during hospital admission. The microscopic analysis showed that both neurons and glial cells are affected in the ischemic focus. Neuronal death in the ischemic focus was mostly caused by cell necrosis and only about 10% by apoptosis. Regarding vascular lesions, it was observed that the most frequent HP lesion of intracerebral arterioles was arteriosclerosis. The lumen of the arterioles was reduced, and the vascular endothelium had a discontinuous aspect, which indicates a change in the blood-brain barrier. Sometimes the arteriole lumen was completely obstructed, with fibrinoid necrosis in the internal and middle tunic, or with the proliferation of fibroblasts and the formation of young intraluminal connective tissue. Intraparenchymal blood capillaries in the ischemic area showed endothelium discontinuities, lumen collapse, and sometimes massive perivascular edema. As for neuroinflammation, the presence of numerous neutrophils, lymphocytes, plasma cells and macrophages was found in the ischemic focus, forming a complex and inhomogeneous cellular mixture. Of the inflammatory cells present in the ischemic focus and in the ischemic penumbra area, the most numerous were the macrophages. The HP analysis showed that neuroinflammation is very complex and different in intensity from one patient to another, most likely due to associated comorbidities, age, treatment administered until death, etc.


Absence of confounding does not correspond to collapsibility of the rate ratio or rate difference.
Miettinen and Cook (Am J Epidemiol 1981; 114:593-603) showed that absence of confounding does not imply collapsibility of the odds ratio; that is, the crude odds ratio need not equal a common stratum-specific odds ratio even if the exposed and unexposed study groups have the same distribution of risk factors. Less well known is that absence of confounding does not correspond to collapsibility of the person-time rate ratio or rate difference. For example, two study groups can have the same distribution of all risk factors and yet the crude rate ratio need not equal a common stratum-specific rate ratio. The present paper provides an example and explanation of this phenomenon. The discrepancy between nonconfounding and collapsibility in rate comparisons arises when person-time is a post-exposure variable whose distribution can be altered by the effects of exposure and other risk factors.


[Catalytic characteristics of 5'-nucleotidase in the structure of cell membrane rafts in smooth muscles].
5'-nucleotidase (EN 220.127.116.11) is widely distributed enzyme occurring in vertebrate, bacterial and plant cells. The main physiological function of 5'-nucleotidase is hydrolysis of 5'-AMP to adenosine and Pi. It was found that the detergent-insoluble membrane domains (rafts) are enriched by proteins possessing high 5'-AMPase activity. This study is aimed to investigate some physical and chemical properties of 5'-nucleotidase, which is present in detergent insoluble membrane domains isolated from pig stomach and lung. It was shown for the first time that catalytic properties of the raft-associated 5'-nucleotidase and of the pure enzyme described in literature differ. Our results demonstrate that the greatest activity of the raft-associated enzyme takes place in the physiological conditions contrary to the pure enzyme. Our data suggest that such changes of 5'-nucleotidase catalytic activity might be due to the disruption of its interaction with membrane rafts.


Is it all about the self? The effect of self-control depletion on ultimatum game proposers.
In the ultimatum-game, as in many real-life social exchange situations, the selfish motive to maximize own gains conflicts with fairness preferences. In the present study we manipulated the availability of cognitive-control resources for ultimatum-game proposers to test whether preference for fairness is a deliberative cognitive-controlled act or an automatic act. In two experiments we found that a shortage of cognitive control (ego depletion) led proposers in the ultimatum game (UG) to propose significantly more equal split offers than non-depleted proposers. These results can be interpreted as resulting from an automatic concern for fairness, or from a greater fear of rejection, which would be in line with a purely self-interested response. To separate these competing explanations, in Experiment 2 we conducted a dictator-game in which the responder cannot reject the offer. In contrast to the increased fairness behavior demonstrated by depleted ultimatum-game proposers, we found that depleted dictator-game allocators chose the equal split significantly less often than non-depleted allocators. These results indicate that fairness preferences are automatically driven among UG proposers. The automatic fair behavior, however, at least partially reflects concern about self-interest gain. We discuss different explanations for these results.


Abdominal pain and anorectal disease in AIDS.
The diagnosis and treatment of abdominal pain and anorectal disease in AIDS patients are discussed. Emphasis is placed on the practical aspects of patient care.


Trichuris muris as a tool for holistic discovery research: from translational research to environmental bio-tagging.
Trichuris spp. (whipworms) are intestinal nematode parasites which cause chronic infections associated with significant morbidities. Trichuris muris in a mouse is the most well studied of the whipworms and research on this species has been approached from a number of different disciplines. Research on T. muris in a laboratory mouse has provided vital insights into the host–parasite interaction through analyses of the immune responses to infection, identifying factors underpinning host susceptibility and resistance. Laboratory studies have also informed strategies for disease control through anthelmintics and vaccine research. On the contrary, research on naturally occurring infections with Trichuris spp. allows the analysis of the host–parasite co-evolutionary relationships and parasite genetic diversity. Furthermore, ecological studies utilizing Trichuris have aided our knowledge of the intricate relationships amongst parasite, host and environment. More recently, studies in wild and semi-wild settings have combined the strengths of the model organism of the house mouse with the complexities of context-dependent physiological responses to infection. This review celebrates the extraordinarily broad range of beneficiaries of whipworm research, from immunologists and parasitologists, through epidemiologists, ecologists and evolutionary biologists to the veterinary and medical communities.


The Long-Term Consequences of a Golden Nest: Socioeconomic Status in Childhood and the Age at Leaving Home.
The age at leaving the parental home has significant implications for social and economic outcomes across the life course, highlighting the importance of examining nest-leaving patterns. We study the role of childhood standard of living on the age at nest leaving. Using data from the Survey of Health, Ageing and Retirement in Europe (SHARE), we show empirically that individuals who grow up in families with a higher socioeconomic status-that is, in a golden nest-leave the parental home later than others. Given that better-off individuals tend to obtain more education, and that young adults generally leave the parental home after completing their education, we also find that a higher level of education delays nest leaving. Nonetheless, the positive relationship between socioeconomic status and nest-leaving age still holds for given education levels, across European countries characterized by different cultural traits, for both males and females, and among urban and rural residents. We use a three-period life cycle model to show that this behavior is consistent with standard assumptions about preferences and resources if earnings increase with age. Moreover, habit-forming preferences that assume that utility depends on the gap between current and past consumption reinforce the delaying effect of a golden nest on nest leaving.


Endoscopic endonasal approach to the infraorbital nerve with nasolacrimal duct preservation.
Objectives Infraorbital nerve (ION) decompression, excision to remove intrinsic tumors, and resection with oncological margins in malignancies with perineural invasion or dissemination are usually accomplished with an open approach. The objective is to describe the surgical anatomy, technique, and indications of the endonasal endoscopic approach (EEA) to the ION with nasolacrimal duct preservation. Design Eleven sides of formalin-fixed specimens were dissected. An anterior maxillary antrostomy was performed. The length of the ION prominence within the sinus and anatomic features of the covering bone were studied. A 45-degree endoscope visualized the infraorbital prominence endonasally. An angled dissector and dural blade allowed for dissection and resection of the ION ipsilaterally and contralaterally. Results The bone features of the ION prominence allowed for ipsilateral dissection in 10 out of 11 sides. In one case with the ION surrounded by thick cortical bone, the dissection could only be started by drilling contralaterally. The 45-degree endoscope visualized 92.2% and 100% of the length of the nerve using the ipsilateral and contralateral nostrils, respectively. Ipsilaterally, 83% of its length was resected, and 96.3% was resected contralaterally. Conclusion The ION can be approached using an ipsilateral EEA with nasolacrimal duct preservation in most cases. The contralateral approach provides a wider angle to access the ION. This technique is primarily indicated in cases where the EEA can be used for tumor resection and oncological margins within the ION.


Genome-wide DNA polymorphisms in two cultivars of mei (Prunus mume sieb. et zucc.).
Mei (Prunus mume Sieb. et Zucc.) is a famous ornamental plant and fruit crop grown in East Asian countries. Limited genetic resources, especially molecular markers, have hindered the progress of mei breeding projects. Here, we performed low-depth whole-genome sequencing of Prunus mume 'Fenban' and Prunus mume 'Kouzi Yudie' to identify high-quality polymorphic markers between the two cultivars on a large scale. A total of 1464.1 Mb and 1422.1 Mb of 'Fenban' and 'Kouzi Yudie' sequencing data were uniquely mapped to the mei reference genome with about 6-fold coverage, respectively. We detected a large number of putative polymorphic markers from the 196.9 Mb of sequencing data shared by the two cultivars, which together contained 200,627 SNPs, 4,900 InDels, and 7,063 SSRs. Among these markers, 38,773 SNPs, 174 InDels, and 418 SSRs were distributed in the 22.4 Mb CDS region, and 63.0% of these marker-containing CDS sequences were assigned to GO terms. Subsequently, 670 selected SNPs were validated using an Agilent's SureSelect solution phase hybridization assay. A subset of 599 SNPs was used to assess the genetic similarity of a panel of mei germplasm samples and a plum (P. salicina) cultivar, producing a set of informative diversity data. We also analyzed the frequency and distribution of detected InDels and SSRs in mei genome and validated their usefulness as DNA markers. These markers were successfully amplified in the cultivars and in their segregating progeny. A large set of high-quality polymorphic SNPs, InDels, and SSRs were identified in parallel between 'Fenban' and 'Kouzi Yudie' using low-depth whole-genome sequencing. The study presents extensive data on these polymorphic markers, which can be useful for constructing high-resolution genetic maps, performing genome-wide association studies, and designing genomic selection strategies in mei.