Cooperative optical pattern formation in an ultrathin atomic layer.
Spontaneous pattern formation from a uniform state is a widely studied nonlinear optical phenomenon that shares similarities with non-equilibrium pattern formation in other scientific domains. Here we show how a single layer of atoms in an array can undergo nonlinear amplification of fluctuations, leading to the formation of intricate optical patterns. The origin of the patterns is intrinsically cooperative, eliminating the necessity of mirrors or cavities, although introduction of a mirror in the vicinity of the atoms significantly modifies the scattering profiles. The emergence of these optical patterns is tied to a bistable collective response, which can be qualitatively described by a long-wavelength approximation, similar to a nonlinear Schrödinger equation of optical Kerr media or ring cavities. These collective excitations have the ability to form singular defects and unveil atomic position fluctuations through wave-like distortions.


Treatment of vocal fold bowing using neuromuscular electrical stimulation.
To investigate the clinical effectiveness and safety of a novel behavioral voice therapy program combining structured vocal exercise with adjunctive neuromuscular electrical stimulation for rehabilitating dysphonia secondary to vocal fold bowing. Prospective interventional clinical case series with a 3-month follow-up. Outpatient speech and hearing clinic in an academic medical center. Convenience sample of 7 patients diagnosed by an otolaryngologist as having chronic dysphonia for at least 3 months due to bilateral vocal fold bowing. A novel voice therapy program incorporating exercise principles and sustained phonations of increasing length, volume, and pitch paired with concurrent transcutaneous neuromuscular electrical stimulation. Change in maximum phonation time, highest attainable pitch, glottal closure, supraglottic compression, and Voice Handicap Index. Maximum phonation time for /i/ increased significantly (z = -2.201, P < .03), with a modest effect demonstrated (Hedges g, 0.65; 95% confidence interval, -0.56 to 1.75). Voice Handicap Index trended toward significance (z = -1.787, P < .07). Glottal closure during phonation improved, and supraglottic compression decreased. Improvements were maintained or enhanced at the 3-month follow-up. Analysis of highest attainable pitch data was limited owing to aperiodicity in the baseline evaluations. Behavioral voice therapy with adjunctive neuromuscular electrical stimulation reduced vocal fold bowing, resulting in improved acoustic, laryngeal, and patient-centered outcomes. Maximum phonation time and glottal closure results imply increased vocal fold tension secondary to enhanced thyroarytenoid or cricothyroid muscle function after voice therapy.


Dystrophin and Dp71, two products of the DMD gene, show a different pattern of expression during embryonic development in zebrafish.
Dystrophin, the protein defective in Duchenne muscular dystrophy (DMD), plays a critical role in the formation and maintenance of the neuromuscular junction. In addition to dystrophin, activation of internal promoters of the DMD gene leads to the production of several short products. Among these, Dp71, which consists of the C-terminal domain of dystrophin, is the most abundant product of the gene in non-muscle tissues and brain. In this report, we compare the temporal and regional expression patterns of dystrophin and Dp71 at different stages of embryonic development and during retinal differentiation in zebrafish. The Dp71 transcripts are the earliest to be expressed at 9-10 h post-fertilization (hpf) in the axial mesoderm. As development proceeds, intense Dp71 staining is observed in the notochord, the developing brain, the marginal regions of the somites and the eye primordium. At the completion of retinal differentiation, Dp71 is expressed in the ganglion and inner nuclear layers. Transcripts encoding dystrophin have a slightly later onset of expression, 13-14 hpf, and remain restricted to the transverse myosepta through all the developmental stages examined. The complementary patterns of expression of dystrophin and Dp71 suggest that these two proteins exert different functions during embryonic development in zebrafish.


Evolutionary and functional properties of a two-locus beta-globin polymorphism in Indian house mice.
Electrophoretic surveys of hemoglobin (Hb) polymorphism in house mice from South Asia and the Middle East have revealed that two alternative beta-globin haplotypes, Hbb(d) and Hbb(p), are often present at intermediate frequencies in geographically disparate populations. Both haplotypes harbor two functionally distinct beta-globin paralogs, HBB-T1 (which encodes the beta-chain subunits of the major Hb isoform) and HBB-T2 (which encodes the beta-chains of the minor Hb isoform). The Hbb(d) and Hbb(p) haplotypes share identical HBB-T1 alleles, but products of the alternative HBB-T2 alleles (d(minor) and p(minor)) are distinguished by two amino acid substitutions. To investigate the possible adaptive significance of the Hbb(d)/Hbb(p) polymorphism we conducted a population genetic analysis of the duplicated beta-globin genes of Indian house mice (Mus castaneus) in conjunction with experimental studies of Hb function in inbred strains of mice that carry the alternative Hbb(d) and Hbb(p) haplotypes. The main objectives of this study were (i) to characterize patterns of nucleotide polymorphism and linkage disequilibrium in the duplicated beta-globin genes of M. castaneus, (ii) to test the hypothesis that the Hbb(d) and Hbb(p) haplotypes are maintained as a balanced polymorphism, and (iii) to assess whether allelic differences in the alternative minor Hb isoforms (d(minor) and p(minor)) are associated with different O(2)-binding properties. A multilocus analysis of polymorphism and divergence revealed that levels of diversity at the HBB-T2 gene exceeded neutral expectations, and reconstructed haplotype networks for both beta-globin paralogs revealed extensive allele sharing with several other closely related species of Mus. However, despite this suggestive evidence for balancing selection, O(2)-equilibrium curves revealed no discernible functional differences between red cell lysates containing the d(minor) and p(minor) Hb isoforms. If the d(minor) and p(minor) alleles are maintained as a balanced polymorphism, our results indicate that the associated fitness variance is not directly related to respiratory functions of Hb.


A delayed rectifier conductance in type I hair cells of the mouse utricle.
1. Membrane currents of hair cells in acutely excised or cultured mouse utricles were recorded with the whole cell voltage-clamp method at temperatures between 23 and 36 degrees C. 2. Type I and II hair cells both had delayed rectifier conductances that activated positive to -55 mV. 3. Type I, but not type II, hair cells had an additional delayed rectifier conductance (gK,L) with an activation range that was unusually negative and variable. At 23-25 degrees C, V(1/2) values ranged from -88 to -62 mV in 57 cells. 4. gK,L was very large. At 23-25 degrees C, the average maximum chord conductance was 75 +/- 65 nS (mean +/- SD, n = 57; measured at -54 mV), or approximately 21 nS/pF of cell capacitance. 5. gK,L was highly selective for K+ over Na+ (permeability ratio PNa+/PK+:0.006), but unlike other delayed rectifiers, gK,L was significantly permeable to Cs+ (PCs+/PK+:0.31). gK,L was independent of extracellular Ca2+. 6. At -64 mV, Ba2+ and 4-aminopyridine blocked gK,L with apparent dissociation constants of 2.0 mM and 43 microM, respectively. Extracellular Cs+ (5 mM) blocked gK,L by 50% at -124 mV. Apamin (100 nM) and dendrotoxin (10 nM) has no effect. 7. The kinetic data of gK,L are consistent with a sequential gating model with at least two closed states and one open state. The slow activation kinetics (principal time constants at 23-25 degrees C:600-200 ms) had a thermal Q10 of 2.1. Inactivation (Q10:2.7) was partial at all temperatures. Deactivation followed a double-exponential time course and had a Q10 of 2.0. 8. At 23-25 degrees C, gK,L was appreciably activated at the mean resting potential of type I hair cells (-77 +/- 3.1 mV, n = 62), so that input conductances were often more than an order of magnitude larger than those of type II cells. If these conditions hold in vivo, type I cells would produce unusually small receptor potentials. Warming the cells to 36 degrees C produced parallel shifts in gK,L's activation range (0.8 +/- 0.3 mV/degrees C, n = 8), and in the resting potential (0.6 +/- 0.3 mV/degrees C, n = 4). Thus the high input conductances were not an artifact of unphysiological temperatures but remained high near body temperature. It remains possible that in vivo gK,L's activation range is less negative and input conductances are lower; the large variance in the voltage range of activation suggests that it may be subject to modulation.


Activation of manipulation and function knowledge during visual search for objects.
This study aimed at comparing the time course of the activation of function and manipulation knowledge during object identification. The influence of visual similarity and context information was also assessed. In 3 eye-tracking experiments, conducted with the Visual-World-Paradigm, participants heard the name of an object and had to identify it among four pictures. The target object (e.g., shopping cart) could be presented along with objects related by (a) function (e.g., basket), (b) manipulation (e.g., lawnmower), (c) context (e.g., cash register), (d) visual similarity (e.g., toaster), and (e) completely unrelated objects. Growth curve analyses were used to assess competition effects among semantically (a, b, and c), visually related (d), and unrelated competitors (e). Results showed that manipulation- and function-related, but not context-related objects received more fixations than the unrelated ones, with a temporal advantage for the manipulation-related objects (Experiment 1). However, the visually similar objects faded the semantic competition effects, especially for function-related objects (Experiment 2). Finally, no temporal differences appeared when manipulation- and function-related objects were shown within the same visual array (Experiment 3). These results support the idea that both function and manipulation are relevant features of object semantic representations, but in the absence of other semantic competitors the activation of manipulation features appears prioritized during object identification. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Voltage-sensitive dye imaging of neuronal populations under hyperbaric conditions: preliminary results obtained using a new technique.
We used voltage-sensitive dye imaging to study the properties of transient large-scale neuronal populations under hyperbaric conditions using a newly-developed high-pressure optical cell. In our experiments we investigated propagation of neuronal voltage wave depolarization along the CA2-CA1 Schaffer collateral pathway in rat hippocampal slices. The voltage-sensitive dye responses were studied at pressures up to 20 atmospheres (atm) over a range in which changes in excitability and pressure-reversal of narcosis/anesthesia have been described to occur in animals. An electrode placed in the CA2 region was used to evoke a signal along the Schaffer collateral neuronal circuit toward CA1 using a paired pulse paradigm (PPF). Initial inspection of the data indicates that the signal amplitude of the excitation following the second PPF event is enhanced at high pressure. Data analysis using MatLab software revealed a range of conductance velocities between different layers within the Schaffer collateral and for sites at different distances from the stimulating electrode. The estimated value of the conductance velocity along the trajectory of maximum flow is in good agreement with previous determinations of axonal propagation along the Schaffer collateral.


Effectiveness of a spontaneous carvacrol nanoemulsion against Salmonella enterica Enteritidis and Escherichia coli O157:H7 on contaminated broccoli and radish seeds.
The incidence of foodborne illness associated with the consumption of fresh produce has continued to increase over the past decade. Sprouts, such as mung bean, alfalfa, radish, and broccoli, are minimally processed and have been sources for foodborne illness. Currently, a 20,000 ppm calcium hypochlorite soak is recommended for the treatment of sprouting seeds. In this study, the efficacy of an antimicrobial carvacrol nanoemulsion was tested against Salmonella enterica subspecies enterica serovar Enteritidis (ATCC BAA-1045) or EGFP expressing Escherichia coli O157:H7 (ATCC 42895) contaminated sprouting seeds. Antimicrobial treatments were performed by soaking inoculated seeds in nanoemulsions (4000 or 8000 ppm) for 30 or 60 min. Following treatment, surviving cells were determined by performing plate counts and/or Most Probable Number (MPN) enumeration. Treated seeds were sprouted and tested for the presence of pathogens. Treatment successfully inactivated low levels (2 and 3 log CFU/g) of S. Enteritidis and E. coli on radish seeds when soaked for 60 min at concentrations ≥4000 (0.4%) ppm carvacrol. This treatment method was not affective on contaminated broccoli seeds. Total sprout yield was not influenced by any treatments. These results show that carvacrol nanoemulsions may be an alternative treatment method for contaminated radish seeds.


Multi-state model for studying an intermediate event using time-dependent covariates: application to breast cancer.
The aim of this article is to propose several methods that allow to investigate how and whether the shape of the hazard ratio after an intermediate event depends on the waiting time to occurrence of this event and/or the sojourn time in this state. A simple multi-state model, the illness-death model, is used as a framework to investigate the occurrence of this intermediate event. Several approaches are shown and their advantages and disadvantages are discussed. All these approaches are based on Cox regression. As different time-scales are used, these models go beyond Markov models. Different estimation methods for the transition hazards are presented. Additionally, time-varying covariates are included into the model using an approach based on fractional polynomials. The different methods of this article are then applied to a dataset consisting of four studies conducted by the German Breast Cancer Study Group (GBSG). The occurrence of the first isolated locoregional recurrence (ILRR) is studied. The results contribute to the debate on the role of the ILRR with respect to the course of the breast cancer disease and the resulting prognosis. We have investigated different modelling strategies for the transition hazard after ILRR or in general after an intermediate event. Including time-dependent structures altered the resulting hazard functions considerably and it was shown that this time-dependent structure has to be taken into account in the case of our breast cancer dataset. The results indicate that an early recurrence increases the risk of death. A late ILRR increases the hazard function much less and after the successful removal of the second tumour the risk of death is almost the same as before the recurrence. With respect to distant disease, the appearance of the ILRR only slightly increases the risk of death if the recurrence was treated successfully. It is important to realize that there are several modelling strategies for the intermediate event and that each of these strategies has restrictions and may lead to different results. Especially in the medical literature considering breast cancer development, the time-dependency is often neglected in the statistical analyses. We show that the time-varying variables cannot be neglected in the case of ILRR and that fractional polynomials are a useful tool for finding the functional form of these time-varying variables.


Glycopeptides of the type-common glycoprotein gD of herpes simplex virus types 1 and 2.
We have carried out detailed structural studies of the glycopeptides of glycoprotein gD of herpes simplex virus types 1 and 2. We first examined and compared the number of N-asparagine-linked oligosaccharides present in each glycoprotein. We found that treatment of either pgD-1 or pgD-2 with endo-beta-N-acetylglucosaminidase H (Endo H) generated three polypeptides which migrated more rapidly than pgD on gradient sodium dodecyl sulfate-polyacrylamide gels. Two of the faster-migrating polypeptides were labeled with [(3)H]mannose, suggesting that both pgD-1 and pgD-2 contained three N-asparagine-linked oligosaccharides. Second, we characterized the [(3)H]mannose-labeled tryptic peptides of pgD-1 and pgD-2. We found that both glycoproteins contained three tryptic glycopeptides, termed glycopeptides 1, 2, and 3. Gel filtration studies indicated that the molecular weights of these three peptides were approximately 10,000, 3,900, and 1,800, respectively, for both pgD-1 and pgD-2. Three methods were employed to determine the size of the attached oligosaccharides. First, the [(3)H]mannose-labeled glycopeptides were treated with Endo H, and the released oligosaccharide was chromatographed on Bio-Gel P6. The size of this molecule was estimated to be approximately 1,200 daltons. Second, Endo H treatment of [(35)S]methionine-labeled glycopeptide 2 reduced the molecular size of this peptide from approximately 3,900 to approximately 2,400 daltons. Third, glycopeptide 2 isolated from the gD-like molecule formed in the presence of tunicamycin was approximately 2,200 daltons. From these experiments, the size of each N-asparagine-linked oligosaccharide was estimated to be approximately 1,400 to 1,600 daltons. Our experiments indicated that glycopeptides 2 and 3 each contained one N-asparagine-linked oligosaccharide chain. Although glycopeptide 1 was large enough to accommodate more than one oligosaccharide chain, the experiments with Endo H treatment of the glycoprotein indicated that there were only three N-asparagine-linked oligosaccharides present in pgD-1 and pgD-2. Further studies of the tryptic glycopeptides by reverse-phase high-performance liquid chromatography indicated that all of the glycopeptides were hydrophobic in nature. In the case of glycopeptide 2, we observed that when the carbohydrate was not present, the hydrophobicity of the peptide increased. The properties of the tryptic glycopeptides of pgD-1 were compared with the properties predicted from the deduced amino acid sequence of gD-1. The size and amino acid composition compared favorably for glycopeptides 1 and 2. Glycopeptide 3 appeared to be somewhat smaller than would be predicted from the deduced sequence of gD-1. It appears that all three potential glycosylation sites predicted by the amino acid sequence are utilized in gD-1 and that a similar number of glycosylation sites are present in gD-2.


Templated repair of long bone defects in rats with bioactive spiral-wrapped electrospun amphiphilic polymer/hydroxyapatite scaffolds.
Effective repair of critical-size long bone defects presents a significant clinical challenge. Electrospun scaffolds can be exploited to deliver protein therapeutics and progenitor cells, but their standalone application for long bone repair has not been explored. We have previously shown that electrospun composites of amphiphilic poly(d,l-lactic acid)-co-poly(ethylene glycol)-co-poly(d,l-lactic acid) (PELA) and hydroxyapatite (HA) guide the osteogenic differentiation of bone marrow stromal cells (MSCs), making these scaffolds uniquely suited for evaluating cell-based bone regeneration approaches. Here we examine whether the in vitro bioactivity of these electrospun scaffolds can be exploited for long bone defect repair, either through the participation of exogenous MSCs or through the activation of endogenous cells by a low dose of recombinant human bone morphogenetic protein-2 (rhBMP-2). In critical-size rat femoral segmental defects, spiral-wrapped electrospun HA-PELA with preseeded MSCs resulted in laminated endochondral ossification templated by the scaffold across the longitudinal span of the defect. Using GFP labeling, we confirmed that the exogenous MSCs adhered to HA-PELA survived at least 7 days postimplantation, suggesting direct participation of these exogenous cells in templated bone formation. When loaded with 500 ng of rhBMP-2, HA-PELA spirals led to more robust but less clearly templated bone formation than MSC-bearing scaffolds. Both treatment groups resulted in new bone bridging over the majority of the defect by 12 weeks. This study is the first demonstration of a standalone bioactive electrospun scaffold for templated bone formation in critical-size long bone defects.


Delirium in critical illness: clinical manifestations, outcomes, and management.
Delirium is the most common manifestation of brain dysfunction in critically ill patients. In the intensive care unit (ICU), duration of delirium is independently predictive of excess death, length of stay, cost of care, and acquired dementia. There are numerous neurotransmitter/functional and/or injury-causing hypotheses rather than a unifying mechanism for delirium. Without using a validated delirium instrument, delirium can be misdiagnosed (under, but also overdiagnosed and trivialized), supporting the recommendation to use a monitoring instrument routinely. The best-validated ICU bedside instruments are CAM-ICU and ICDSC, both of which also detect subsyndromal delirium. Both tools have some inherent limitations in the neurologically injured patients, yet still provide valuable information about delirium once the sequelae of the primary injury settle into a new post-injury baseline. Now it is known that antipsychotics and other psychoactive medications do not reliably improve brain function in critically ill delirious patients. ICU teams should systematically screen for predisposing and precipitating factors. These include exacerbations of cardiac/respiratory failure or sepsis, metabolic disturbances (hypoglycemia, dysnatremia, uremia and ammonemia) receipt of psychoactive medications, and sensory deprivation through prolonged immobilization, uncorrected vision and hearing deficits, poor sleep hygiene, and isolation from loved ones so common during COVID-19 pandemic. The ABCDEF (A2F) bundle is a means to facilitate implementation of the 2018 Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS) Guidelines. In over 25,000 patients across nearly 100 institutions, the A2F bundle has been shown in a dose-response fashion (i.e., greater bundle compliance) to yield improved survival, length of stay, coma and delirium duration, cost, and less ICU bounce-backs and discharge to nursing homes.


[Properties of the excitatory postsynaptic currents in the cat motor neurons].
Monosynaptic supraspinal and la excitatory postsynaptic current (e. p. s. c.) recorded with the aid of voltage clamp technique at different levels of MP, revealed characteristics as follows: peak amplitude 2--18 nA, rise time 0.3--0.5 msec, half-width 0.5--1.0 msec; extrapolated reversal potential +70-+100 mV. Slow residual current (1--4 nA) followed the e. p. s. c. E. p. s. c. and e. p. s. p. s were discussed considering the current-voltage relation and analog model.


Field-stepped broadband NMR in pulsed magnets and application to SrCu2(BO3)2 at 54T.
Pulsed magnets generate the highest magnetic fields as brief transients during which the observation of NMR is difficult, however, this is the only route to unique insight into material properties up to the regime of 100T. Here, it is shown how rather broad NMR spectra can be assembled in a pulsed magnet during a single field pulse by using the inherent time dependence of the field for the recording of field-stepped free induction decays that cover a broad frequency range. The technique is then applied to (11)B NMR of the spin-dimer system SrCu2(BO3)2, a magnetic insulator known to undergo a series of field-driven changes of the magnetic ground state. At peak fields of about 54T at the Dresden High Magnetic Field Laboratory, (11)B NMR spectra spanning a total of about 9MHz width are reconstructed. The results are in good accordance with a change from a high-temperature paramagnetic state to a low-temperature commensurate superstructure of field-induced spin-dimer triplets.


Trends in chemical ecology revealed with a personal computer program for searching data bases of scientific references and abstracts.
A compiled program, JCE-REFS.EXE (coded in the QuickBASIC language), for use on IBM-compatible personal computers is described. The program converts a DOS text file of current B-I-T-S (BIOSIS Information Transfer System) or BIOSIS Previews references into a DOS file of citations, including abstracts, in a general style used by scientific journals. The latter file can be imported directly into a word processor or the program can convert the file into a random access data base of the references. The program can search the data base for up to 40 text strings with Boolean logic. Selected references in the data base can be exported as a DOS text file of citations. Using the search facility, articles in theJournal of Chemical Ecology from 1975 to 1991 were searched for certain key words in regard to semiochemicals, taxa, methods, chemical classes, and biological terms to determine trends in usage over the period. Positive trends were statistically significant in the use of the words: semiochemical, allomone, allelochemic, deterrent, repellent, plants, angiosperms, dicots, wind tunnel, olfactometer, electrophysiology, mass spectrometry, ketone, evolution, physiology, herbivore, defense, and receptor. Significant negative trends were found for: pheromone, vertebrates, mammals, Coleoptera, Scolytidae,Dendroctonus, lactone, isomer, and calling.


Benefits of Elective Para-Aortic Radiotherapy for pN1 Prostate Cancer Using Arc Therapy (Intensity-Modulated or Volumetric Modulated Arc Therapy): Protocol for a Nonrandomized Phase II Trial.
In patients with prostate cancer (PCa) with histopathologically proven pelvic lymph node (LN) metastasis (pN1) after extended pelvic lymph node dissection (ePLND), multimodality treatment consisting of treatment of the primary tumor and whole pelvic radiotherapy (WPRT) combined with androgen deprivation therapy (ADT) offers promising results, leading to better cause-specific survival rates compared with ADT alone. However, in case more than one pelvic LN is invaded by the tumor, approximately 40% of the patients relapse biochemically and clinically. Clinical relapse is present in the para-aortic LNs (M1a disease) in up to 77% of the relapsing cases. We hypothesize that, based on the evidence that positive LNs represent the door to hematogenous dissemination, elective para-aortic irradiation will reduce the development of both retroperitoneal nodal (M1a) and distant metastasis (M1b or M1c disease), postpone the need for palliative ADT, and prolong the time to castration-refractory disease. To test this hypothesis, we will conduct a prospective, nonrandomized phase II trial to study the efficacy of additional elective para-aortic radiotherapy (PART) in pN1 patients compared with those who were historically treated with adjuvant WPRT alone. We aim to include 137 patients with PCa and presence of pN1 disease after ePLND. With this number of patients, an improvement of 15% in the 5-year clinical relapse-free survival can be detected with a power of 80%. Recruitment of patients for this trial started in 2017 and will be completed approximately by March 2020. This is the first phase II trial to investigate the benefits of an elective PART in patients with PCa. The results of this trial will potentially serve as a sound base for a later randomized phase III trial. All participants are given a PART information sheet and required to give written informed consent. Results are expected to be published in a peer-reviewed journal. ClinicalTrials.gov NCT03079323; https://clinicaltrials.gov/ct2/show/NCT03079323 (Archived by WebCite at http://www.webcitation.org/73ELimv1d). PRR1-10.2196/11256.


[The effect of new synthetic prostanoids on the indices of the blood coagulation system].
In the experiments on rabbits it was shown, that the administration of prostanoids IOS 3933 caused a reduction of ADP- and collagen induced platelet aggregation, platelet adhesion to collagen and elevation of t-PA level. This prostanoid prevented both a decrease in platelet count and reduction of AT III activity, but did not affect the protein C level during thromboplastin infusion.


Gaboxadol in angelman syndrome: A double-blind, parallel-group, randomized placebo-controlled phase 3 study.
To evaluate efficacy and safety of gaboxadol for treatment of children with Angelman syndrome (AS). In this international, double-blind, phase 3 trial, we randomized children 4-12 years old with a molecular diagnosis of AS and a Clinical Global Impression (CGI)-severity score ≥3 to either daily administration of weight-based gaboxadol or matching placebo for 12 weeks. The primary endpoint was the CGI-Improvement-AS (CGI-I-AS) score at week 12. Secondary endpoints included the proportion of participants with CGI-I-AS response of ≤3 (i.e., at least "minimal improvement") and ≤2 (i.e., at least "much improvement") at week 12. Safety and tolerability were monitored throughout the study. Weight based dosing of study drug ranged from 0.125 mg/kg to 0.24 mg/kg depending on weight range. Between August 2019 and November 2020, 104 participants were enrolled: participants 4-12 years old were randomly (1:1) assigned to gaboxadol (n = 47) or placebo (n = 50), and 7 other participants 2─3 years old who received gaboxadol and were assessed for safety only. All gaboxadol-treated participants and 48 of 50 placebo-treated participants completed treatment. There was no significant difference in CGI-I-AS between groups: at week 12, mean CGI-I-AS score was 3.3 (SD, 1.00) and 3.2 (SD, 1.05) in the gaboxadol and placebo groups, respectively, yielding a least squares mean difference of zero (p = 0.83). There were no between-group significant differences with respect to CGI-I-AS responses. Gaboxadol was well tolerated in all age groups of this study. There was no significant difference in CGI-I-AS between gaboxadol and placebo after 12 weeks of study treatment in pediatric AS participants. GOV: NCT04106557.


Modification of an automated method for determining plasma and erythrocyte cholinesterase activity in laboratory animals.
By altering the analytical parameters on an automated analyzer, analytical precision for measuring cholinesterase (ChE) activity in hemolysates was markedly improved in samples from several species. Manual and automated spectrophotometric analyses of plasma and erythrocyte ChE activity were optimized for use in rats, mice and dogs. Replicate ChE analyses were performed on plasma samples and on hemolysates made from whole blood or packed erythrocytes to determine the precision of the manual ChE method and 4 modifications of the automated method. Large method-related differences in precision were observed for the erythrocyte assay, but not the plasma assay. The addition of a nonionic detergent to make hemolysates was beneficial in determining erythrocyte ChE activity in the rat, but not in the mouse or dog. Species specific temperature conversion factors were necessary for comparing results from methods using different analytical temperatures. Analysis of whole blood hemolysates provided similar or better precision for determining erythrocyte ChE activity compared to using hemolysates made from packed erythrocytes. Comparisons of erythrocyte ChE results obtained from assays with even minor methodological differences should be approached with caution because of the many analytical factors which can affect results.


Physical standards for scuba divers.
Scuba diving has become a popular aquatic sport during the past 2 decades, and family physicians are frequently involved in examining scuba divers and in the decision making that allows them to pursue their training or careers in this sport. The purpose of this article is to review the physiology and gas laws that are involved in diving and to provide guidelines for assessing each diving candidate. The clinical manifestations of decompression sickness are discussed as well as the medical problems that could cause severe morbidity or mortality if diving is attempted.


What Becomes of Giant Vortices in the Abelian Higgs Model.
We discuss vortex solutions of the Abelian Higgs model in the limit of large winding number n. We suggest a framework where a topological quantum number n is associated with a ratio of dynamical scales and a systematic expansion in inverse powers of n is then derived in the spirit of effective field theory. The general asymptotic form of giant vortices is obtained. For critical coupling the axially symmetric vortices become integrable in the large-n limit and we present the corresponding analytic solution. The method provides simple asymptotic formulas for the vortex shape and parameters with accuracy that can be systematically improved, and can be applied to topological solitons of other models. After including the next-to-leading terms the approximation works remarkably well down to n=1.


Metastatic malignant disease of unknown origin.
The charts of 106 patients with metastasis from an unknown primary cancer were reviewed to formulate a more appropriate investigative strategy than is presently employed. The spinal column was the most common site for initial presentation of metastatic disease (26.5 percent). The primary tumor was identified before death in 31.3 percent of patients and after death in 6.6 percent. Lung cancer was found in 40 percent of patients with identified primary tumors. Diagnostic studies directed at specific symptoms had a significantly greater yield. Electroencephalograms, gallium scans, thyroid scans, and mammograms were not useful as screening studies. Conversely, bone scans were positive in 46.5 percent of asymptomatic patients and in 88 percent of symptomatic patients. Chest roentgenograms were suggestive of malignant tumors in 43.6 percent of patients. Results of liver scans were predictable on the basis of changes in the alkaline phosphatase level and clinical liver examination. History and physical examination should clearly document the stage of disease, evaluate possible primary sites, and rule out impending acute complications. Chest roentgenograms and bone scans should be obtained early and open biopsy of accessible lesions scheduled promptly. Efforts should be directed at ruling out the more treatable malignant tumors. Further work-up is then indicated only by the development of specific symptomatology. Since median patient survival after initial presentation is only 6.6 months, prolonged hospitalization for numerous nonproductive diagnostic tests seems inappropriate.


[Experimental study of relations of the argasid ticks Alveonasus lahorensis with Coxiella burnetii].
The argasid ticks A. lahorensis can be infected with Coxiella burnetii on feeding on an infected rabbit. The adoptive pathogen reproduces in the ticks and accumulates in them up to 10(10) ID50 g(-1). Coxiella persists in the ticks at this level up to 156 days (the time of observation). The infected ticks transmit Coxiella to guinea pigs while sucking. The ticks show transovarial transmission of Coxilla during metamorphosis. On this basis and with consideration for the fact that A. lahorensis uses a wide host range, it can long starve and retains Coxiella burnetii in the foci of Q fever.


C reactive protein and immunoglobulin G in synovial fluid and serum in joint disease.
C reactive protein (CRP) and immunoglobulin G (IgG) were measured in synovial fluid and serum of 72 patients (29 with rheumatoid arthritis (RA), 17 with osteoarthritis, 11 with crystal synovitis, seven with undifferentiated arthritis, and eight with seronegative arthritis). The synovial fluid:serum (SF:S) ratios were compared with those calculated from the SF:S ratios of transferrin, caeruloplasmin, and alpha 2 macroglobulin, using the binomial test within groups and the Mann-Whitney test between groups. In RA synovial fluid CRP concentrations were lower than expected and IgG concentrations higher than expected. In osteoarthritis CRP concentrations were higher than expected. In seronegative arthritis IgG concentrations were raised. The ratio of CRP:IgG was depressed in RA. These findings are consistent with a role for CRP in the inflammatory process of RA, while the CRP:IgG ratio may be of value in the differential diagnosis of joint disease.


Angioedema Spotlight: A Closer Examination of Sacubitril/Valsartan Safety Results.
Incorporation of neprilysin inhibition into heart failure pharmacotherapy regimens has recently been recommended by U.S. guidelines, based on results from the PARADIGM-HF trial comparing sacubitril/valsartan to enalapril. While most of the discussion has focused on efficacy, a closer examination of the safety results, particularly the incidence of angioedema during the run-in and double-blind periods, is also warranted. Although no major safety concerns were identified, an angioedema risk comparable to enalapril was found, primarily in the black population. Therefore, despite combination with an angiotensin receptor blocker, which historically has a lower incidence of angioedema, the addition of neprilysin inhibition yields an angioedema risk profile comparable to angiotensin converting enzyme (ACE) inhibitors. Clinicians should recognize this safety risk when prescribing sacubitril/valsartan and remain vigilant in counseling patients regarding the signs and symptoms of angioedema. As recommended by the guidelines, avoiding sacubitril/valsartan use concurrently or within 36 hours of the last dose of an ACE inhibitor or in patients with a history of angioedema is also crucial to minimize angioedema risk and prevent patient harm.


Structural polypeptides of simian rotavirus SA11 and the effect of trypsin.
Analysis of purified simian rotavirus has shown that it contains fewer structural polypeptide classes than previously reported. Two polypeptides (molecular weights, 62,000 and 28,000) commonly found in purified rotaviruses were, in fact, produced by cleavage of a larger structural polypeptide (molecular weight, about 88,000) by trypsin, which is usually employed to increase the yield of rotaviruses in tissue culture. Trypsin-uncleaved, double-shelled rotaviruses are probably composed of only five polypeptide classes; three in the inner layer, and two in the outer layer.


Towards Patient-Specific 3D-Printed Robotic Systems for Surgical Interventions.
Surgical robots have been extensively researched for a wide range of surgical procedures due to the advantages of improved precision, sensing capabilities, motion scaling, and tremor reduction, to name a few. Though the underlying disease condition or pathology may be the same across patients, the intervention approach to treat the condition can vary significantly across patients. This is especially true for endovascular interventions, where each case brings forth its own challenges. Hence it is critical to develop patient-specific surgical robotic systems to maximize the benefits of robot-assisted surgery. Manufacturing patient-specific robots can be challenging for complex procedures and furthermore the time required to build them can be a challenge. To overcome this challenge, additive manufacturing, namely 3D-printing, is a promising solution. 3D-printing enables fabrication of complex parts precisely and efficiently. Although 3D-printing techniques have been researched for general medical applications, patient-specific surgical robots are currently in their infancy. After reviewing the state-of-the-art in 3D-printed surgical robots, this paper discusses 3D-printing techniques that could potentially satisfy the stringent requirements for surgical interventions. We also present the accomplishments in our group in developing 3D-printed surgical robots for neurosurgical and cardiovascular interventions. Finally, we discuss the challenges in developing 3D-printed surgical robots and provide our perspectives on future research directions.


Histone deacetylation is required for orderly meiosis.
Histone acetylation is associated with a diversity of chromatin-related processes in mitosis. However, its roles in mammalian oocyte meiosis are largely unknown. In the present study, we first investigated in detail the acetylation changes during porcine oocyte maturation using a panel of antibodies specific for the critical acetylated forms of histone H3 and H4, and showed meiosis stage-dependent and lysine residue-specific patterns of histone acetylation. By using trichostatin A (TSA), a general inhibitor of histone deacetylases (HDACs), we further determined that selective inhibition of histone deacetylation (thereby maintaining hyperacetylation) delayed the onset of germinal vesicle breakdown and produced a high frequency of lagging chromosomes or chromatin bridges at anaphase and telophase I (AT-I), suggesting that histone deacetylation is required for orderly meiotic resumption and accurate chromosome segregation in porcine oocytes. In addition, we examined the localization and expression of HDAC1 by performing immunofluorescence and immunoblotting analysis. The results showed that subcellular translocation, expression level and phosphorylated modification of HDAC1 were temporally regulated and likely to coparticipate in the establishment of histone acetylation profiles in oocyte meiosis.


[Antioxidant properties of remaxol, reamberin, and ademetionine in patients with drug-induced liver injury on the background of antituberculous therapy].
The antioxidant properties of remaxol, reamberin and ademetionine have been studied in comparison to 5 % glucose solution in a group of 120 patients with drug-induced liver injury. It is established that the inclusion of this drugs in the composition of complex therapy contributed to restoration of the antioxidant potential of the cells, which was manifested by increased activity of glutathione peroxidase and superoxide dismutase and integral indices of antioxidant protection (total antioxidant capacity and total antioxidant status) with a relative stabilization of the level of glutathione-S-transferase. Maximum pharmacotherapeutic effect with respect to all of the studiea indices has been achieved by the use of remaxol.


Local delivery of mutant CCL2 protein-reduced orthopaedic implant wear particle-induced osteolysis and inflammation in vivo.
Total joint replacement (TJR) has been widely used as a standard treatment for late-stage arthritis. One challenge for long-term efficacy of TJR is the generation of ultra-high molecular weight polyethylene wear particles from the implant surface that activates an inflammatory cascade which may lead to bone loss, prosthetic loosening and eventual failure of the procedure. Here, we investigate the efficacy of local administration of mutant CCL2 proteins, such as 7ND, on reducing wear particle-induced inflammation and osteolysis in vivo using a mouse calvarial model. Mice were treated with local injection of 7ND or phosphate buffered saline (PBS) every other day for up to 14 days. Wear particle-induced osteolysis and the effects of 7ND treatment were evaluated using micro-CT, histology, and immunofluorescence staining. Compared with the PBS control, 7ND treatment significantly decreased wear particle-induced osteolysis, which led to a higher bone volume fraction and bone mineral density. Furthermore, immunofluorescence staining showed 7ND treatment decreased the number of recruited inflammatory cells and osteoclasts. Together, our results support the feasibility of local delivery of 7ND for mitigating wear particle-induced inflammation and osteolysis, which may offer a promising strategy for extending the life time of TJRs.


Haloferula luteola sp. nov., an endophytic bacterium isolated from the root of a halophyte, Rosa rugosa, and emended description of the genus Haloferula.
A Gram-negative, non-spore-forming, endophytic bacterium, strain YC6886(T), was isolated from the root of a halophyte, Rosa rugosa, which inhabits coastal areas of Namhae Island off the southern coast of Korea. Cells were non-motile, obligately aerobic rods and formed pale-yellow colonies. The isolate grew at 4-32 °C (optimum 25-28 °C) and at pH 6.5-9.5 (optimum pH 7.5) and grew optimally with 2-3 % (w/v) NaCl, but NaCl was not an absolute requirement for growth. Strain YC6886(T) produced yellow carotenoid pigments. Strain YC6886(T) exhibited the highest 16S rRNA gene sequence similarity with Haloferula sargassicola MN1-1037(T) (97.4 %). Sequence similarities between strain YC6886(T) and other members of the genus Haloferula were 93.9-94.7 %. DNA-DNA relatedness between strain YC6886(T) and H. sargassicola KCTC 22202(T) and Haloferula rosea KCTC 22201(T) was 27 and 15 %, respectively. The major fatty acids were iso-C(14 : 0), C(16 : 0) and C(16 : 1)ω9c and minor components were C(14 : 0), C(18 : 0) and anteiso-C(15 : 0). The major respiratory quinone was menaquinone 9 and the DNA G+C content was 58.5 mol%. The polar lipid profile was composed of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, an unknown phospholipid and an unknown phosphoglycolipid. On the basis of phenotypic, chemotaxonomic, DNA-DNA hybridization and phylogenetic analysis, strain YC6886(T) represents a novel species in the genus Haloferula, for which the name Haloferula luteola sp. nov. is proposed. The type strain is YC6886(T) ( = KCTC 22447(T) = DSM 21608(T)). An emended description of the genus Haloferula is also presented.


Development of a 96-well plate sample preparation method for integrated N- and O-glycomics using porous graphitized carbon liquid chromatography-mass spectrometry.
Changes in glycosylation signatures of cells have been associated with pathological processes in cancer as well as infectious and autoimmune diseases. The current protocols for comprehensive analysis of N-glycomics and O-glycomics derived from cells and tissues often require a large amount of biological material. They also only allow the processing of very limited numbers of samples at a time. Here we established a workflow for sequential release of N-glycans and O-glycans based on PVDF membrane immobilization in 96-well format from 5 × 105 cells. Released glycans are reduced, desalted, purified, and reconstituted, all in 96-well format plates, without additional staining or derivatization. Glycans are then analyzed with porous graphitized carbon nano-liquid chromatography coupled to tandem mass spectrometry using negative-mode electrospray ionization, enabling the chromatographic resolution and structural elucidation of glycan species including many compositional isomers. The approach was demonstrated using glycoprotein standards and further applied to analyze the glycosylation of the murine mammary gland NMuMG cell line. The developed protocol allows the analysis of N- and O-glycans from relatively large numbers of samples in a less time consuming way with high repeatability. Inter- and intraday repeatability of the fetuin N-glycan analysis showed two median intraday coefficients of variations (CVs) of 7.6% and 8.0%, and a median interday CV of 9.8%. Median CVs of 7.9% and 8.7% for the main peaks of N- and O-glycans released from the NMuMG cell line indicate a very good repeatability. The method is applicable to purified glycoproteins as well as to biofluids and cell- or tissue-based samples.


Singlet-triplet excitations in the unconventional spin-Peierls TiOBr compound.
We have performed time-of-flight neutron scattering measurements on powder samples of the unconventional spin-Peierls compound TiOBr using the fine-resolution Fermi chopper spectrometer (SEQUOIA) at the Spallation Neutron Source at Oak Ridge National Laboratory. These measurements reveal two branches of magnetic excitations within the commensurate and incommensurate spin-Peierls phases, which we associate with n=1 and n=2 triplet excitations out of the singlet ground state. These results represent the first direct measurement of the singlet-triplet energy gap in TiOBr, which has a value of E(g)=21.2±1.0 meV.


Nanomaterials-Enabled Physicochemical Antibacterial Therapeutics: Toward the Antibiotic-Free Disinfections.
Bacterial infection continues to be an increasing global health problem with the most widely accepted treatment paradigms restricted to antibiotics. However, the overuse and misuse of antibiotics have triggered multidrug resistance of bacteria, frustrating therapeutic outcomes, and leading to higher mortality rates. Even worse, the tendency of bacteria to form biofilms on living and nonliving surfaces further increases the difficulty in confronting bacteria because the extracellular matrix can act as a robust barrier to prevent the penetration of antibiotics and resist environmental damage. As a result, the inability to eliminate bacteria and biofilms often leads to persistent infection, implant failure, and device damage. Therefore, it is of paramount importance to develop alternative antimicrobial agents while avoiding the generation of bacterial resistance to prevent the large-scale growth of bacterial resistance. In recent years, nano-antibacterial materials have played a vital role in the antibacterial field because of their excellent physical and chemical properties. This review focuses on new physicochemical antibacterial strategies and versatile antibacterial nanomaterials, especially the mechanism and types of 2D antibacterial nanomaterials. In addition, this advanced review provides guidance on the development direction of antibiotic-free disinfections in the antibacterial field in the future.


[Perspectives of the control of Opisthorchis invasion by the method of treating the molluskan population].
Sanitation of the mollusk population with highly effective cercaricide preparations can be used for the control of opisthorchosous infection. Low concentrations of molluskocides which are sublethal for non-infected mollusks have turned to be lethal for hyperinfected individuals. All tested molluskocides display a cercaricide effect in concentrations which are considerably lower than molluskocide ones. Low concentrations of cercaricides are toxic both for cercariae and parthenites from the liver of mollusks and for freely swimming cercariae. Disastrously affecting the freely swimming cercariae microdoses of cercaricides prevent the infection of the second intermediate hosts. Microdoses of cercaricides which are lethal for cercariae are not toxic for the majority of hydrobionts including fishes of all age groups. As far as the dynamics of the infection level of Bithynia with O. felineus is characterized by a one-peak curve with a distinct peak in the middle-end of July the treatment of water bodies with microdoses of cercaricides should be carried out just in this period.


A failure to confirm the effectiveness of a brief group psychoeducational program for mothers of children with high-functioning pervasive developmental disorders: a randomized controlled pilot trial.
The purpose of this study was to examine the effectiveness of group psychoeducation to relieve the psychological distress of mothers of children with high-functioning pervasive developmental disorders (HFPDD) and to improve the behaviors of the children. Seventy-two mothers of preschool outpatients with HFPDD were randomly assigned to a four-session brief group psychoeducational program (GP). The sessions were held every second week in addition to the usual treatment (GP + treatment as usual [TAU] group), or to a TAU-alone group. The primary outcome was self-reported symptoms of maternal mental health as assessed using the 28-item General Health Questionnaire (GHQ-28) at 21 weeks post-randomization (week 21). The GHQ-28 at the end of the intervention (week 7), Aberrant Behavior Checklist (ABC) for the behavior of the children, the Zarit Burden Interview (ZBI), and the Medical Outcomes Study 36-item Short Form Health Survey (SF-36) were carried out at weeks 7 and 21. We tested the group effects with the interaction between the intervention and the evaluation points. The GHQ-28 score at week 21 was significantly higher in the GP + TAU group as compared to that in the TAU-alone group, indicating a greater improvement in the TAU-alone group. There was no evidence that GP + TAU led to a greater improvement of maternal mental health than TAU-alone at week 7. Similarly, no evidence was obtained to indicate that GP + TAU led to a reduction in the ABC or ZBI scores by week 7 or 21. The adjusted scores for the RF (role emotional) and MH (mental health) subscales of the SF-36 at week 21 were also significantly lower in the GP + TAU group, indicating a similar tendency to that of the change of the GHQ-28 score at week 21. The psychoeducational program did not alleviate maternal distress, aberrant behaviors of the children, or caregiver burden.


Gene expression analysis defines the proximal tubule as the compartment for endocytic receptor-mediated uptake in the Xenopus pronephric kidney.
Endocytic receptors in the proximal tubule of the mammalian kidney are responsible for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones, and they can mediate drug-induced nephrotoxicity. In this paper, we report the first evidence indicating that the pronephric kidneys of Xenopus tadpoles are capable of endocytic transport. We establish that the Xenopus genome harbors genes for the known three endocytic receptors megalin/LRP2, cubilin, and amnionless. The Xenopus endocytic receptor genes share extensive synteny with their mammalian counterparts. In situ hybridizations demonstrated that endocytic receptor expression is highly tissue specific, primarily in the pronephric kidney, and did not occur prior to neurulation. Expression was strictly confined to proximal tubules of the pronephric kidney, which closely resembles the situation reported in mammalian kidneys. By immunohistochemistry, we demonstrated that Xenopus pronephric tubule epithelia express high amounts of the endocytic receptors megalin/lrp2 and cubilin in the apical plasma membrane. Furthermore, functional aspects of the endocytic receptors were revealed by the vesicular localization of retinol-binding protein in the proximal tubules, probably representing endocytosed protein. In summary, we provide here the first comprehensive report of endocytic receptor expression, including amnionless, in a nonmammalian species. Remarkably, renal endocytic receptor expression and function in the Xenopus pronephric kidney closely mirrors the situation in the mammalian kidney. The Xenopus pronephric kidney therefore represents a novel, simple model for physiological studies on the molecular mechanisms underlying renal tubular endocytosis.


HIF1 transcription factor regulates laminin-332 expression and keratinocyte migration.
Epidermal wound repair is a complex process involving the fine orchestrated regulation of crucial cell functions, such as proliferation, adhesion and migration. Using an in vitro model that recapitulates central aspects of epidermal wound healing, we demonstrate that the transcription factor HIF1 is strongly stimulated in keratinocyte cultures submitted to mechanical injury. Signals generated by scratch wounding stabilise the HIF1alpha protein, which requires activation of the PI3K pathway independently of oxygen availability. We further show that upregulation of HIF1alpha plays an essential role in keratinocyte migration during the in vitro healing process, because HIF1alpha inhibition dramatically delays the wound closure. In this context, we demonstrate that HIF1 controls the expression of laminin-332, one of the major epithelial cell adhesion ligands involved in cell migration and invasion. Indeed, silencing of HIF1alpha abrogates injury-induced laminin-332 expression, and we provide evidence that HIF1 directly regulates the promoter activity of the laminin alpha3 chain. Our results suggest that HIF1 contributes to keratinocyte migration and thus to the re-epithelialisation process by regulating laminin-332.


[Current Indications for Surgery in Small Cell Lung Cancer].
Small cell lung cancer (SCLC) is characterised by an aggressive and rapid growth, with a tendency towards early metastatic spread. It has one of the worst prognoses of all malignancies. Though radio-chemotherapy is still considered the mainstay of therapy due to its high sensitivity, increasing evidence, supported by a number of retrospective analyses and large case series, suggests that surgery may play a significant role in the treatment of SCLC within a multimodality treatment concept. In this context, surgery can provide overall survival benefit and improve local control in selected cases. Currently, an operation can be recommended if the SCLC manifests as a single peripheral node, in early cancer stages (T1 - 2, N0, M0), in cases of mixed histological tumour types but also in selected cases in chemotherapy-resistant tumors. In the light of the current availability of immunotherapy by checkpoint inhibitors, resection of SCLC should also be considered on the basis of the expression of checkpoint receptors that might have relevant impact on therapy and prognosis of the course of SCLC. In order to fulfil the above-mentioned criteria and to provide a higher level of evidence and to develop guidelines, randomised controlled trials need to be performed.


Neuroanatomic and functional correlates of depressed mood: the Cardiovascular Health Study.
Although a number of studies suggest an association between stroke and depression, few have examined the relation between magnetic resonance imaging (MRI)-identified lesions and depression among community-dwelling older adults. This cross-sectional study sought to assess the association between MRI infarcts in the basal ganglia and non-basal-ganglia areas, potential functional consequences of these lesions, and depressive symptomatology in 3,371 US men and women aged 65 years or older who participated in the Cardiovascular Health Study between 1992 and 1994. By using multiple linear regression models, the authors found that after adjustment for age, gender, and stroke history, Center for Epidemiologic Studies Depression Scale scores were independently associated with non-basal-ganglia lesions (p = 0.04) but were not independently associated with basal ganglia lesions (p = 0.11). When measures of physical disability and cognitive impairment were added to the models, these measures displaced MRI-identified infarcts in their association with depressive symptoms. In additional models, hemispheric location and size of the basal ganglia lesion were found to have no relation to depression levels. These results suggest that the functional consequences of cerebrovascular disease may be the causal pathway by which basal ganglia and non-basal-ganglia lesions are associated with depressive symptomatology.


Can more be learned from selection experiments of value in animal breeding programmes? Or is it time for an obituary?
Selection experiments in laboratory animals and livestock have provided a wealth of information on genetic parameters of quantitative traits and on the effectiveness of selection in the short and long term on both directly selected and correlated traits. They have stimulated developments in theory and tests of it, and extreme selected lines continue to be source material for biological study. Some of the main questions and findings are briefly reviewed. Yet much of successful animal breeding practice has been based essentially on statistical methods, assuming where necessary the infinitesimal model, and new developments such as genomic selection are similarly not based on selection experiments. Information on the genetic architecture of quantitative traits is provided by selection experiments, but new methods for deeper studies of the biology are available. I discuss the future role for selection experiments in view of changes in funding streams and technology and conclude that there is little case for starting new experiments, but retention of existing long-term lines is desirable and DNA should be collected from all lines on a continuing basis.


The prognostic significance of EBV DNA load and EBER status in diagnostic specimens from diffuse large B-cell lymphoma patients.
Epstein-Barr virus (EBV)-encoded small RNA in situ hybridization (EBER-ISH) is a widely accepted method to evaluate EBV involvement in diffuse large B-cell lymphoma (DLBCL), although little is known regarding associations between EBV DNA load and the EBER status and whether EBV DNA load data provide additional clinical information. In this study, we quantified EBV DNA load in diagnostic specimens from DLBCL patients diagnosed at our hospital to evaluate clinical implications of EBV DNA load in diagnostic specimens as contrasted with EBER-ISH. Among 140 DLBCL patients without underlying immunodeficiency, 51 were evaluable for both EBER and EBV DNA load, 83 for EBER only and one for EBV DNA load only. The median EBV DNA load was 708 copies/µg. Although EBV DNA load was significantly higher for EBER-positive patients than for EBER-negative patients (p < 0.001), EBV DNA was detected in up to 72% of EBER-negative patients. Progression-free survival and overall survival were significantly worse for patients with EBV DNA load above 700 copies/µg than for those with EBV DNA load below 700 copies/µg (p = 0.009 and p = 0.003); they were also significantly worse for EBER-positive patients than for EBER-negative patients (p < 0.001 and p = 0.001). Even among EBER-negative patients, higher EBV DNA load conferred worse progression-free survival and overall survival (p = 0.041 and p = 0.013). These findings indicate that EBV DNA load in diagnostic specimens is not a simple surrogate for the EBER status and may be a potential biomarker associated with EBV involvement and prognosis in DLBCL. Copyright © 2015 John Wiley & Sons, Ltd.


Block of endplate channels by permeant cations in frog skeletal muscle.
Motor endplates of frog semitendinosus muscles were studied under voltage clamp. Current fluctuations induced by iontophoretic application of acetylcholine were analyzed to give the elementary conductance, gamma , and mean open time, tau , of endplate channels. Total replacement of the external Na+ ion by several other metal ions and by many permeant organic cations changed both gamma and tau . Except with NH4+ ions, the gamma values with foreign test ions were all smaller than expected from the independence relation and their previously measured permeability ratios. The more hydrophobic ions gave the smallest gamma values. Foreign permeant cations also depress gamma when mixed with Na+ ions. These effects could be interpreted in terms of binding of ions to a saturable site within the endplate channel as they pass through. The site for organic ions would have a hydrophobic component. Similar evidence is given for a metal ion binding site on the cytoplasmic end of the channel accessible to internal ions. Most foreign cations also shortened tau when applied externally. The changes of gating did not seem to be correlated with changes in gamma . Thus there is no evidence for control of tau by ions bound within the pore.


Inhibitory Mechanisms of CME-1, a Novel Polysaccharide from the Mycelia of Cordyceps sinensis, in Platelet Activation.
Objective: CME-1 is a polysaccharide purified from the mycelia of medicinal mushroom Cordyceps sinensis, its molecular weight was determined to be 27.6 kDa by using nuclear magnetic resonance and gas chromatography-mass spectrometry. The initiation of arterial thromboses is relevant to various cardiovascular diseases (CVDs) and is believed to involve platelet activation. Our recent study exhibited that CME-1 has potent antiplatelet activity via the activation of adenylate cyclase/cyclic AMP ex vivo and in vivo. Methods: The aggregometry, and immunoblotting were used in this study. Results: In this study, the mechanisms of CME-1 in platelet activation is further investigated and found that CME-1 inhibited platelet aggregation as well as the ATP-release reaction, relative intracellular [Ca+2] mobilization, and the phosphorylation of phospholipase C (PLC)γ2 and protein kinase C (PKC) stimulated by collagen. CME-1 has no effects on inhibiting either convulxin, an agonist of glycoprotein VI, or aggretin, an agonist of integrin α2β1 stimulated platelet aggregation. Moreover, this compound markedly diminished thrombin and arachidonic acid (AA) induced phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 2, c-Jun N-terminal kinase 1, and Akt. Treatment with SQ22536, an inhibitor of adenylate cyclase, markedly diminished the CME-1-mediated increasing of cyclic AMP level and reversed prostaglandin E1- or CME-1-mediated inhibition of platelet aggregation and p38 MAPK and Akt phosphorylation stimulated by thrombin or AA. Furthermore, phosphodiesterase activity of human platelets was not altered by CME-1. Conclusion: The crucial finding of this study is that the antiplatelet activity of CME-1 may initially inhibit the PLCγ2-PKC-p47 cascade, and inhibit PI3-kinase/Akt and MAPK phosphorylation through adenylate cyclase/cyclic AMP activation, then inhibit intracellular [Ca+2] mobilization, and, ultimately, inhibit platelet activation. The novel role of CME-1 in antiplatelet activity indicates that this compound exhibits high therapeutic potential for treating or preventing CVDs.


A Novel Human Activity Recognition and Prediction in Smart Home Based on Interaction.
Smart Homes are generally considered the final solution for living problem, especially for the health care of the elderly and disabled, power saving, etc. Human activity recognition in smart homes is the key to achieving home automation, which enables the smart services to automatically run according to the human mind. Recent research has made a lot of progress in this field; however, most of them can only recognize default activities, which is probably not needed by smart homes services. In addition, low scalability makes such research infeasible to be used outside the laboratory. In this study, we unwrap this issue and propose a novel framework to not only recognize human activity but also predict it. The framework contains three stages: recognition after the activity, recognition in progress, and activity prediction in advance. Furthermore, using passive RFID tags, the hardware cost of our framework is sufficiently low to popularize the framework. In addition, the experimental result demonstrates that our framework can realize good performance in both activity recognition and prediction with high scalability.


Extracellular Cyclophilin A, Especially Acetylated, Causes Pulmonary Hypertension by Stimulating Endothelial Apoptosis, Redox Stress, and Inflammation.
Oxidative stress and inflammation play key roles in the development of pulmonary arterial hypertension (PAH). Cyclophilin A (CypA) is secreted in response to oxidative stress and promotes inflammation and cardiovascular disease. Endothelial cell (EC) dysfunction is an early event in the pathogenesis of PAH. We evaluated the role of extracellular CypA in PAH and compared the effects of acetylated CypA (AcK-CypA, increased by oxidative stress) and CypA on EC dysfunction. In transgenic mice that express high levels of CypA in EC specifically, a PAH phenotype was observed at 3 months including increased right ventricular systolic pressure, α-smooth muscle actin expression in small arterioles, and CD45-positive cells in the lungs. Mechanistic analysis using cultured mouse pulmonary microvascular EC and human pulmonary microvascular EC showed that extracellular CypA and AcK-CypA stimulated EC inflammatory signals: increased VCAM1 (vascular cell adhesion molecule 1) and ICAM1 (intercellular adhesion molecule 1), phosphorylation of p65, and degradation of IkB. Extracellular CypA and AcK-CypA increased EC apoptosis measured by TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining, Apo-ONE assay, and caspase 3 cleavage. Oxidative stress stimulated CypA and AcK-CypA secretion, which further promoted EC oxidative stress. AcK-CypA, compared with CypA, stimulated greater increases in apoptosis, inflammation, and oxidative stress. MM284, a specific inhibitor of extracellular CypA, attenuated EC apoptosis induced by CypA and AcK-CypA. EC-derived CypA (especially AcK-CypA) causes PAH by a presumptive mechanism involving increased EC apoptosis, inflammation, and oxidative stress. Our results suggest that inhibiting secreted extracellular CypA is a novel therapeutic approach for PAH.


Effects of GPR81 silencing combined with cisplatin stimulation on biological function in hypopharyngeal squamous cell carcinoma.
Hypopharyngeal squamous cell carcinoma (HSCC) is a malignant tumor found in the head and neck region. Lactate receptor 1, also known as G protein‑coupled receptor81 (GPR81), has been reported to play a vital role in cancer growth and metabolism. However, the function of GPR81 in HSCC remains largely unknown. The present study investigated the effect of GPR81 on cell survival and GPR81‑mediated energy metabolism under cisplatin treatment in HSCC. GPR81 knockdown reduced the proliferation and invasion of the human HSCC cell line FaDu. Furthermore, GPR81 silencing combined with cisplatin treatment increased the expression of translocase of outer mitochondrial membrane 20 at the mRNA and protein levels (P<0.05). mRNA and protein expression of phosphofructokinase 1 in mRNA appeared to be downregulated in GPR81 knockdown FaDu cells treated with cisplatin, although this was not statistically significant. GPR81 silencing and cisplatin challenge showed no significant upregulation compared with the control, but significant downregulation in mRNA and protein levels compared with the shRNA‑scramble group. Apoptosis was measured by flow cytometry with annexin V and 7‑aminoactinomycin D. GPR81 silencing and cisplatin led to an increased apoptotic rate. Moreover, absence of GPR81 combined with cisplatin exposure increased caspase‑3 expression and decreased Bcl‑2 levels. The results of the present study suggested that GPR81 and cisplatin sensitivity played an important role in HSCC growth and metabolism.


Electromagnetically induced transparency and ultraslow optical solitons in a coherent atomic gas filled in a slot waveguide.
We investigate the electromagnetically induced transparency (EIT) and nonlinear pulse propagation in a Λ-type three-level atomic gas filled in a slot waveguide, in which electric field is strongly confined inside the slot of the waveguide due to the discontinuity of dielectric constant. We find that EIT effect can be greatly enhanced due to the reduction of optical-field mode volume contributed by waveguide geometry. Comparing with the atomic gases in free space, the EIT transparency window in the slot waveguide system can be much wider and deeper, and the Kerr nonlinearity of probe laser field can be much stronger. We also prove that using slot waveguide ultraslow optical solitons can be produced efficiently with extremely low generation power.


Guided run-and-tumble active particles: wall accumulation and preferential deposition.
Bacterial biofilms cost an enormous amount of resources in the health, medical, and industrial sectors. To understand early biofilm formation, beginning from planktonic states of active suspensions (such as Escherichia coli) to micro-colonization, it is vital to study the mechanics of cell accumulation near surfaces and subsequent deposition. Variability in bacterial motion strategies and the presence of taxis fields make the problem even more multifaceted. In this study, analytical expressions for the density and angular distributions, mean orientation, and deposition rates in such bacterial suspensions are derived, with and without the effects of external guiding or taxis fields. The derived results are closely verified by simulations of confined active particles using run-and-tumble statistics from multiple past experiments and utilizing a preferential sticking probability model for deposition. The behavioral changes in cell running strategies are modeled by varying the run-time distribution from an exponential to a heavy-tailed one. It is found that the deposition rates can be altered significantly by a guiding torque but are less affected by a change in the cell running behavior. However, both the mechanisms alter the pair correlation function of the deposited structures. The factor behind the changes in the architecture of deposited biomass under a torque generating guiding field turns out to be an asymmetrical rotational drift of planktonic cells, which can be an important physical mechanism behind the organization in confined active particle suspensions.


Mutations in the circadian gene CLOCK in colorectal cancer.
The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53% of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G(2)-M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis.


Decreased regional brain volume and cognitive impairment in preterm children at low risk.
To investigate whether preterm children with low risk for neurodevelopmental deficits show long-term changes in gray matter (GM) and white matter (WM) volumes compared with term children and to relate these changes to cognitive outcome. MRI was used to evaluate 20 preterm children who were determined to be at low risk for neurodevelopmental deficits and were born between 30 and 34 weeks' gestational age without major neonatal morbidity or cerebral pathology in the neonatal period and 22 matched, term control subjects. Volumetric images were analyzed by means of voxel-based morphometry to identify regional cerebral alterations. Children also underwent cognitive and behavioral/emotional assessments. Preterm children showed global and regional GM volume reductions in several brain areas, including temporal and parietal lobes and concomitant WM volume reductions in the same areas, although only the left temporal regions achieved statistical significance. Global intellectual performance in the preterm group was significantly decreased compared with control subjects. Neither behavioral nor emotional problems were found in the preterm group. In the whole sample, we found a positive correlation between GM volume bilaterally in the middle temporal and in the postcentral gyri with IQ. Positive correlations were observed between GM and gestational age at birth in parietal and temporal cerebral regions and with WM in parietal regions. Preterm birth has an important impact on the neurodevelopmental and cognitive outcome of children at 9 years of age, being a risk factor for decreased regional cortical GM and WM even in preterm children with low risk for neurodevelopmental deficits.


Enhancing mesenchymal stem cell response using uniaxially stretched poly(ε-caprolactone) film micropatterns for vascular tissue engineering application.
Regeneration of tunica media with anisotropic architecture still remains a challenging issue for vascular tissue engineering (TE). Herein, we present the development of flexible poly(ε-caprolactone) (PCL) film micropatterns to regulate mesenchymal stem cells (MSCs) function for tunica media construction. Results showed that uniaxial thermal stretching of PCL films resulted in topographical micropatterns comprising of ridges/grooves, and improved mechanical properties, including yield stress, Young's modulus, and fracture stress without sacrificing film elasticity. Culturing on such PCL film micropatterns, MSCs self-aligned along the ridges with a more elongated morphology as compared to that of the un-stretched film group. Moreover, MSCs obtained a contractile SMCs-like phenotype, with ordered organization of cellular stress filaments and upregulated expression of the contractile makers, including SM-α-actin, calponin, and SM-MHC. The PCL film micropatterns could be rolled into a small-diameter 3D tubular scaffold with circumferential anisotropy of ridges/grooves, and in the incorporation of MSCs, which facilitated a hybrid sandwich-like vascular wall construction with ordered cell architecture similar to that of the tunica media. These results provide insights of how geometric cues are able to regulate stem cells with desired functions and have significant implications for the designing of a functionalized vascular TE scaffold with appropriate topographical geometries for guiding tunica media regeneration with microscale control of cell alignment and genetic expression.


Early and Late Recurrent Epistaxis Admissions: Patterns of Incidence and Risk Factors.
Objective Epistaxis is a common complaint, yet few studies have focused on the incidence and risk factors of recurrent epistaxis. Our objective was to determine the patterns of incidence and risk factors for recurrent epistaxis admission (REA). Study Design Case series with chart review. Settings Single academic center. Subjects and Methods The medical records of patients admitted for epistaxis between 1999 and 2015 were reviewed. The follow-up period was defined as 3 years following initial admission. REAs were categorized as early (30 days) and late (31 days to 3 years) following initial admission. Logistic regression was used to identify potential predictors of REAs. Results A total of 653 patients were included. Eighty-six patients (14%) had REAs: 48 (7.5%) early and 38 (6.5%) late. Nonlinear incidence curve was demonstrated for both early and late REAs. Based on logistic regression, prior nasal surgery and anemia were independent risk factors for early REAs. According to multivariate analysis, thrombocytopenia was significantly associated with late REAs. Conclusion Early and late REAs demonstrate different risk predictors. Knowledge of such risk factors may help in risk stratification for this selected group of patients. All patients at risk should be advised on possible preventive measures. Patients at risk for early REA may benefit from a more proactive approach.


Improving quality of life for patients with terminal respiratory disease.
Chronic respiratory disease is an increasingly prevalent cause of life-limiting illness. Care for patients with terminal respiratory diseases has historically focused on disease-modifying therapies, many of which have little impact on life expectancy. This exclusive focus can detract from attention to patient-physician communication, advance care planning and palliative treatment strategies. Such shortcomings are exacerbated by the prognostic uncertainty inherent in many noncancer diagnoses. With relatively indeterminate prognosis, many clinicians are reluctant to address goals of care and to consider palliative strategies. Unfortunately, the symptom burden caused by terminal respiratory diseases is high, particularly with regard to dyspnea, pain and psychiatric symptoms such as depressed mood and anxiety. In being willing to address goals of care with seriously ill patients, and to include a focus on symptom management in patients' care plans, regardless of concomitant disease-modifying strategies, providers can better address the needs of patients with serious, life-limiting respiratory illnesses.


Oncogenesis as a Selective Force: Adaptive Evolution in the Face of a Transmissible Cancer.
Similar to parasites, malignant cells exploit the host for energy, resources and protection, thereby impairing host health and fitness. Although cancer is widespread in the animal kingdom, its impact on life history traits and strategies have rarely been documented. Devil facial tumour disease (DFTD), a transmissible cancer, afflicting Tasmanian devils (Sarcophilus harrisii), provides an ideal model system to monitor the impact of cancer on host life-history, and to elucidate the evolutionary arms-race between malignant cells and their hosts. Here we provide an overview of parasite-induced host life history (LH) adaptations, then both phenotypic plasticity of LH responses and changes in allele frequencies that affect LH traits of Tasmanian devils in response to DFTD are discussed. We conclude that akin to parasites, cancer can directly and indirectly affect devil LH traits and trigger host evolutionary responses. Consequently, it is important to consider oncogenic processes as a selective force in wildlife.


Lipid Nanoparticle Inclusion Prevents Capsaicin-Induced TRPV1 Defunctionalization.
Capsaicin (CPS) is a highly selective agonist of the transient receptor potential vanilloid type 1 (TRPV1) with a nanomolar affinity. High doses or prolonged exposure to CPS induces TRPV1 defunctionalization and, although this effect is currently used for the treatment of thermal hyperalgesia in chronic pain conditions, it is responsible of detrimental effects, such as denervation of sensory fibers. The aim of the present study was to formulate CPS loaded lipid nanocarriers (CPS-LN) in order to optimize CPS release, thus preventing TRPV1 internalization and degradation. CPS-LNs were formulated and characterized by in vitro studies. The activation of TRPV1 receptors after CPS-LN administration was evaluated by measuring spontaneous pain that was induced by local injection into the plantar surface of the mouse hind-paw. Moreover, the expression of TRPV1 in the skin was evaluated by western blot analysis in CPS-LN injected mice and then compared to a standard CPS solution (CPS-STD). CPS inclusion in LN induced a lower pain response when compared to CPS-STD; further, it prevented TRPV1 down-regulation in the skin, while CPS-STD induced a significant reduction of TRPV1 expression. Drug encapsulation in lipid nanoparticles produced an optimization of CPS release, thus reducing mice pain behavior and avoiding the effects that are caused by TRPV1 defunctionalization related to a prolonged activation of this receptor.


5 kHz Transcranial Alternating Current Stimulation: Lack of Cortical Excitability Changes When Grouped in a Theta Burst Pattern.
Background: Suprathreshold transcranial single pulse electrical stimulation (tES) is painful and not applicable in a repetitive mode to induce plastic after-effects. Objective: In order to circumvent this pain problem, we applied here a 5 kHz transcranial alternating current stimulation (tACS) theta burst protocol with a field intensity of up to 10 mA to the primary motor cortex (M1). Furthermore, we were interested in finding out whether electrical theta burst stimulation (eTBS) is able to induce lasting after-effects on cortical plasticity. Methods: Three different eTBS protocols were applied at 5 mA in a sham controlled, double blinded cross-over design on the M1 region of seventeen healthy subjects during the first part of the study. The second study part consists of three different eTBS protocols ranging from 5 mA to 10 mA and 1 ms to 5 ms sinusoidal bursts, applied to the M1 region of 14 healthy subjects. Results: We were able to apply all eTBS protocols in a safe manner, with only six subjects reporting mild side effects related to the stimulation. However, no eTBS protocol induced lasting effects on muscle- evoked potential (MEP) amplitudes when compared to sham stimulation. Significant inhibition of MEP amplitude was only seen in the lower intensity protocols as compared to baseline. Conclusion: eTBS is a safe method to apply high frequency tACS with up to 10 mA intensity. Future studies need to explore the parameter space to a larger extent in order to assure efficacy.


H2O2-mediated cross-linking between lactoperoxidase and myoglobin: elucidation of protein-protein radical transfer reactions.
The H(2)O(2)-dependent reaction of lactoperoxidase (LPO) with sperm whale myoglobin (SwMb) or horse myoglobin (HoMb) produces LPO-Mb cross-linked species, in addition to LPO and SwMb homodimers. The HoMb products are a LPO(HoMb) dimer and LPO(HoMb)(2) trimer. Dityrosine cross-links are shown by their fluorescence to be present in the oligomeric products. Addition of H(2)O(2) to myoglobin (Mb), followed by catalase to quench excess H(2)O(2) before the addition of LPO, still yields LPO cross-linked products. LPO oligomerization therefore requires radical transfer from Mb to LPO. In contrast to native LPO, recombinant LPO undergoes little self-dimerization in the absence of Mb but occurs normally in its presence. Simultaneous addition of 3,5-dibromo-4-nitrosobenzenesulfonic acid (DBNBS) and LPO to activated Mb produces a spin-trapped radical electron paramagnetic resonance signal located primarily on LPO, confirming the radical transfer. Mutation of Tyr-103 or Tyr-151 in SwMb decreased cross-linking with LPO, but mutation of Tyr-146, Trp-7, or Trp-14 did not. However, because DBNBS-trapped LPO radicals were observed with all the mutants, DBNBS traps LPO radicals other than those involved in protein oligomerization. The results clearly establish that radical transfer occurs from Mb to LPO and suggest that intermolecularly transferred radicals may reside on residues other than those that are generated by intramolecular reactions.


Use of a BJAB-derived cell line for isolation of human herpesvirus 8.
Establishment of latently infected cell lines from primary effusion lymphomas (PEL) presently is the most efficient system for the propagation of clinical strains of human herpesvirus 8 (HHV-8) in culture. Here we describe a new approach to culture productively replicating HHV-8 from patient samples. A BJAB-derived B-cell line, BBF, was found to retain HHV-8 longer, to support the latent and lytic replication programs, and to produce transmissible virus. Supernatants from n-butyrate-treated peripheral blood mononuclear cells of 24 HHV-8-seropositive renal transplant recipients were used to infect BBF cells, and replicating virus was detected in cultures from 11 patients. Moreover, BBF cells infected with saliva strains showed a highly productive profile regardless of the initial viral load, which confirms that infectious HHV-8 can be present in saliva and also suggests that saliva strains may exhibit a high tropism for B lymphocytes. In conclusion, we established an in vitro system that efficiently detects HHV-8 in samples with low viral loads and that produces infectious progeny. BBF cells can be used to propagate HHV-8 from different biological samples as well as to clarify important issues related to virus-cell interactions in a context distinct from endothelial and PEL-derived cell lines.


Sarcocystis infection in an Orang Asli: the second human case from Malaysia.
The second case of Sarcocystis infection in man is reported from an aborigine girl. It was an incidental finding at autopsy and two cysts were seen in the muscle of the oropharyngeal region. The cysts and zoites were similar to those in the previous case reported from Malaysia.


The effect of high and low dosages of paraoxon in beta-naphthoflavone-treated rats.
Aliesterases (carboxylesterases) are serine esterases that can serve a protective role for the target acetylcholinesterase (AChE) during organophosphorus insecticide intoxication because the former esterases are alternate phosphorylation sites. The levels of aliesterase activity in liver and plasma and AChE activity in brain regions were investigated after the intravenous administration of paraoxon (P = O) into female rats. The rats were pretreated intraperitoneally with beta-napthoflavone (BNF), which decreases hepatic aliesterase activity following a 3 day in vivo treatment, and/or tri-o-tolyl phosphate (TOTP) to inhibit aliesterases. The liver aliesterases were inhibited less by P = O in BNF-treated rats than in control rats, which suggests that either BNF exposure may have resulted in aliesterases that are less sensitive to P = O inhibition or BNF may have altered P = O's availability. The BNF treatment did not seem to alter the degree of inhibition of the brain AChE activity following the low dosage of paraoxon (0.04 mg/kg). However, the brain AChE activity in the P = O/TOTP/BNF-treated rats was lower than that in the P = O/TOTP-treated rats, suggesting that BNF also caused changes in systems affecting the disposition of P = O in addition to the changes in the hepatic aliesterases. At the high dosage of paraoxon (0.12 mg/kg), the AChE and aliesterase activities showed a pattern similar to that of the low dosage. This suggests that the aliesterases, as altered by BNF exposure, even when nearly completely inhibited, did not alter the response of the target enzyme, AChE, and, therefore, the magnitude of the toxic response.


Improvement of treatment plans developed with intensity-modulated radiation therapy for concave-shaped head and neck tumors.
To improve dose conformity and normal tissue sparing in patients with concave-shaped head and neck cancers by using tomotherapy and static step-and-shoot intensity-modulated radiation therapy (IMRT) and by comparing results with those of three-dimensional (3D) conformal radiation therapy (CRT) and two-dimensional (2D) radiation therapy. Treatment planning in 10 patients with concave-shaped head and neck tumors was performed by using tomotherapy and step-and-shoot IMRT, 3D CRT, and 2D techniques. IMRT plans were modified by placing "virtual critical structures" in regions outside the target where hot spots occurred. These modified plans were used for comparison because they provided better dose conformity. Critical structures were the spinal cord, the parotid glands, and the mandible. Comparisons were performed by means of dose-volume histograms, clinical target volume (CTV), target covered by 95% isodose (D(95%)), dose received by 5% of the critical structure volume (D(5%)), maximum dose, mean dose, and normal tissue complication probability for critical structures. Original IMRT plans showed more conformal dose distributions than those in 3D CRT and 2D plans. However, hot spots developed in the posterior and anterior neck. Introduction of virtual critical structures in IMRT plans resulted in removal of these hot spots without affecting target coverage. Modified IMRT plans also demonstrated better CTV coverage than that in 3D CRT and 2D plans. The average D(95%) was 97.3% with tomotherapy, 97.1% with step-and-shoot IMRT, 84.7% with 3D CRT, and 69.4% with 2D techniques. D(5%) for the spinal cord changed from approximately 45 Gy with 3D plans and 46 Gy with 2D plans to approximately 28 Gy with IMRT. IMRT demonstrated better target coverage and sparing of critical structures than that of 3D CRT and 2D techniques. Use of virtual critical structures resulted in removal of hot spots around the spinal cord.


Cardiovascular actions and pharmacokinetics of desethyl-N-acetylprocainamide in the dog.
The pharmacokinetic profile and the cardiovascular actions of desethyl-N-acetylprocainamide (NAPADE) were studied in chloralose-urethane anesthetized dogs. NAPADE was given as a 15-min i.v. infusion in doses of 12 and 60 mg/kg. In all cases, the plasma concentration vs. time curve could be resolved into two exponential components, and the distribution and elimination of NAPADE were analyzed with a two-compartmental model. Total apparent volume of distribution was 0.4153 +/- 0.0301 liters/kg (mean +/- S.E.M.) for the 12-mg/kg group and 0.4946 +/- 0.0691 liters/kg for the 60-mg/kg group (P greater than .05). Elimination clearance was 0.0061 +/- 0.0006 liters/min/kg for the 12-mg/kg group and 0.0086 +/- 0.0013 liters/min/kg for the 60-mg/kg group (P greater than .05). The elimination phase half-life (T1/2 beta) was 57.0 +/- 4.1 and 53.1 +/- 3.2 min for the 12- and 60-mg/kg groups, respectively (P greater than .05). Thus, NAPADE exhibited first-order kinetics of distribution and elimination in the dose range studied. Renal clearance of unchanged NAPADE amounted to 45.9 +/- 4% of total plasma clearance. NAPADE had a dose- and concentration-related positive inotropic effect, as measured with a Walton-Brodie gauge sutured to the right ventricle. A 12-mg/kg infusion caused a peak increased in myocardial force of 18.4 +/- 3.6% over base line, whereas a 60-mg/kg infusion caused a peak increase in myocardial force of 48.9 +/- 10% over base line. The positive inotropic effect of NAPADE was sustained for 50 to 90 min.(ABSTRACT TRUNCATED AT 250 WORDS)


[Role of helper T-lymphocytes in modulating the humoral immune response to cholera enterotoxin].
The role of helper T-lymphocytes in the modulation of humoral immune response to sheep red blood cells with choleragen has been studied in vivo, the populations of cooperating marrow cells, formed in mice under the action of hydrocortisone being used as a model. In adoptive transfer marrow cells, taken from mice on day 12 after thymectomy and from mice previously treated with antithymocyte serum, have proved incapable of humoral immune response. Choleragen, similarly to theophylline, normalizes the humoral immune response of marrow cells in thymectomized mice, but inhibits this response in intact ones, while thymosin fraction 2 restores it again, thus abolishing the action of choleragen and theophylline. The opposite effects rendered by choleragen and theophylline on humoral immune response, depending on the hormonal status of the animals and the possibility of influencing these effects by means of thymosin fraction 2 indicate that the population of helper T-lymphocytes are selectively sensitive to changes in the concentration of intracellular cAMP. Their capacity for cooperative interaction in the immune process is regulated by thymic hormones and forms the basis of the mechanism permitting the modulation of humoral immune response with choleragen.


[Preventive action of nicotinamide on the pancreatic antioxidant system in experimental streptozotocin diabetes].
The pancreatic antioxidant system and the effect of the pretreatment with 500 mg/ kg b.w. i.p. nicotinamide were studied in male mice (CBA/J x C57BL/6J)F1 with low-dose streptozotocin-induced diabetes (50 mg/kg b.w. x 5 days). Nicotinamide prevented the development of basal hyperglycaemia, hypoinsulinemia and the growth of superoxide dismutase activity without any impact on the elevated glutathione peroxidase activity and the increase in lipid hydroperoxide level.


A control systems engineering approach for adaptive behavioral interventions: illustration with a fibromyalgia intervention.
The term adaptive intervention has been used in behavioral medicine to describe operationalized and individually tailored strategies for prevention and treatment of chronic, relapsing disorders. Control systems engineering offers an attractive means for designing and implementing adaptive behavioral interventions that feature intensive measurement and frequent decision-making over time. This is illustrated in this paper for the case of a low-dose naltrexone treatment intervention for fibromyalgia. System identification methods from engineering are used to estimate dynamical models from daily diary reports completed by participants. These dynamical models then form part of a model predictive control algorithm which systematically decides on treatment dosages based on measurements obtained under real-life conditions involving noise, disturbances, and uncertainty. The effectiveness and implications of this approach for behavioral interventions (in general) and pain treatment (in particular) are demonstrated using informative simulations.


Airborne fungi in indoor and outdoor of asthmatic patients' home, living in the city of sari.
The aim of this study was identification of fungi in indoor and outdoor of asthmatic patients home environment. Opened plates (containing of Malt extract agar media) were used for isolation of fungi in the air of indoor (n=360) and outdoor (n=180) of 90 asthmatic patients home living in the city of Sari at the level of breathing height. Plates were incubated in room temperature for 7-14 days. Then grown fungi were identified by standard mycological techniques.A total of 1876 colonies with 31 and 1692 colonies with 27 genera of fungi were identified from indoor and outdoor of asthmatic patients' home respectively. The most common fungi isolated were Cladosporium, Aspergillus and Penicillium. Stachibotyris, Oedocephalum, and Stemphillium showed the least frequencies among the isolated fungi.Cladosporium, Aspergillus, Penicillium, and Alternaria as the most common allergenic moulds had the most frequencies in indoor air of the houses of asthmatic patients.