Adsorptive capacity and evolution of the pore structure of alumina on reaction with gaseous hydrogen fluoride.
Brunauer-Emmet-Teller (BET) specific surface areas are generally used to gauge the propensity of uptake on adsorbents, with less attention paid to kinetic considerations. We explore the importance of such parameters by modeling the pore size distributions of smelter grade aluminas following HF adsorption, an industrially important process in gas cleaning at aluminum smelters. The pore size distributions of industrially fluorinated aluminas, and those contacted with HF in controlled laboratory trials, are reconstructed from the pore structure of the untreated materials when filtered through different models of adsorption. These studies demonstrate the presence of three distinct families of pores: those with uninhibited HF uptake, kinetically limited porosity, and pores that are surface blocked after negligible scrubbing. The surface areas of the inaccessible and blocked pores will overinflate estimates of the adsorption capacity of the adsorbate. We also demonstrate, contrary to conventional understanding, that porosity changes are attributed not to monolayer uptake but more reasonably to pore length attenuation. The model assumes nothing specific regarding the Al2O3-HF system and is therefore likely general to adsorbate/adsorbent phenomena.


An interfacially plasticized electro-responsive hydrogel for transdermal electro-activated and modulated (TEAM) drug delivery.
This paper highlights the use of hydrogels in controlled drug delivery, and their application in stimuli responsive, especially electro-responsive, drug release. electro-conductive hydrogels (ECHs) displaying electro-responsive drug release were synthesized from semi-interpenetrating networks (semi-IPNs) containing a poly(ethyleneimine) (PEI) and 1-vinylimidazole (VI) polymer blend as the novel electro-active species. The semi-IPNs are systems comprised of polyacrylic acid (PAA) and poly(vinyl alcohol) (PVA). This paper attempts to investigate the various attributes of the electro-responsive ECHs, through institution of a statistical experimental design. The construction of a Box-Behnken design model was employed for the systematic optimization of the ECH composition. The design model comprised of three variables, viz. poly(ethyleneimine) volume; 1-vinylimidazole volume; and applied voltage, critical to the success of the formulation. Electro-responsive drug release was determined on formulations exposed to varying environments to ascertain the optimal environment for the said desired release. A comparison method of formulation water content and swelling through gravimetric analysis was also conducted. Matrix resilience profiles were obtained as an insight to the ability of the ECH to revert to its original structure following applied stress. Response surface and contour plots were constructed for various response variables, namely electro-responsive drug release, matrix resilience and degree of swelling. The outcomes of the study demonstrated the success of electro-responsive drug release. The findings of the study can be utilized for the development of electro-responsive delivery systems of other drugs for the safer and effective drug delivery. Volumes of poly(ethyleneimine) (>2.6 mL) and 1-vinylimidazole (>0.7 mL), resulted in ideal therapeutic electro-responsive drug release (0.8 mg) for indomethacin. Lower amounts of poly(ethyleneimine) and amounts of 1-vinylimidazole ranging from 0.2 to 0.74 mL are consistent with greater than 1.6 mg release per stimulation. Swelling of <25-45% was seen.


Signal detection theory, the approach of choice: model-based and distribution-free measures and evaluation.
New and old methods of analyzing two-choice experiments with confidence ratings are evaluated. These include the theory of signal detectability (TSD), Luce's choice theory,nonparametric techniques based on areas under receiver-operating characteristic (ROC) functions, andmethods based on S' and omega, proposed by Balakrishnan and his colleagues. New methods for assessing the bias of a complete ROC function are proposed, together with an additional area-based measure of response bias. Area measures of both sensitivity and bias proved the most consistent. Response bias for a full ROC function was larger than bias at the cut point and also provided additional information. Participants showed voluntary control of bias for all measures except omega. Unequal variance versions of TSD and choice models gave similar fits to data, with the choice model closer to an equal variance version. Discrimination data from Balakrishnan (1999) formed the empirical test bed.


PSRO: current status of the professional standards review organization program.
Since Public Law 92-603 was enacted in October 1972 considerable progress has been made in the establishment of Professional Standards Review Organizations (PSROs) for the purpose of determining the necessity, appropriateness, and quality of medical care provided beneficiaries of the major programs authorized in the Social Security Act. Sixty-five conditional PSROs are implementing review in acute care hospitals in their geographic area, and 55 planning groups are developing plans to qualify for conditional PSRO designation. The PSRO hospital review system is based on three interrelated review mechanisms. These are concurrent review, which includes admission certification, and continued stay review through discharge; medical care evaluation studies; and analysis of hospital, practitioner, and patient profiles. This article describes the review system in some detail and the potential opportunities the PSRO program offers to occupational therapists.


Gender, Pain, and Function Associated With Physical Activity After Hospitalization in Persons Living With Dementia.
The purpose of this study was to identify factors that are associated with physical activity after hospitalization in persons living with dementia. Multiple linear regressions were conducted to test factors associated with objective activity levels (sedentary, low, moderate, and vigorous) among 244 patients living with dementia from a randomized controlled trial. Within 48 hours of hospital discharge, time in sedentary behavior was associated with increased pain (β=0.164, P =0.015). Time in low activity was associated with less pain (β=-0.130, P =0.049) and higher physical function (β=0.300, P =<0.001). Time in moderate activity was associated with increased physical function (β=0.190, P =0.008) and male gender (β=0.155, P =0.016). No significant associations of potential factors were found with time in vigorous activity. Our findings suggest that managing or reducing pain, encouraging individual functional level, and gender could influence time spent in physical activity after acute hospitalization in persons living with dementia.


Animal model of systemic sclerosis.
Scleroderma is a fibrotic condition characterized by immunological abnormalities, vascular injury and increased accumulation of extracellular matrix proteins in the skin. Although the etiology of scleroderma has not yet been fully elucidated, a growing body of evidence suggests that extracellular matrix overproduction by activated fibroblasts results from a complex interaction among endothelial cells, lymphocytes, macrophages and fibroblasts, through a number of mediators, such as cytokines, chemokines and growth factors. For a better understanding of the pathophysiology of scleroderma, animal models are important tools. These models reproduce several histological as well as biochemical aspects of human scleroderma, and we can learn a lot through animal studies. On the other hand, it must be emphasized that studying animal models cannot answer all the problems of human scleroderma. In this review, I introduce current insights into the pathogenesis and also recent updates of therapeutic approaches using several animal models of SSc, and discuss their contribution to our understanding of the pathogenesis of, and treatments for, human scleroderma.


Prospects for future advancements in islet cell transplantation.
Islet cell transplantation holds great promise for treating patients with type 1 diabetes mellitus (T1DM), and for preventing unstable metabolic state commonly refereed to as brittle diabetes in patients that undergo pancreatic resection given that it is a relatively noninvasive procedure and an attractive alternative to pancreas transplantation for restoring endogenous insulin secretion. The success of recent clinical trials for allogeneic islet transplantation as well as the increasing centers that perform auto-transplantation is showing that the beta cell replacement therapy for the treatment of patients with diabetes or total pancreatectomy has been firmly established. It needs only to be improved and made more widely available to the millions of desperate patients who search for alternatives to a life of insulin injections, hypoglycemia and the risks of end-organ damage. Steady progress has been achieved in recent years in different areas in the pancreatic islet transplantation process including islet cell processing, preservation, and immune therapies that justify optimism. To implement this therapeutic approach to larger cohorts of patients that would benefit from the restoration of beta cell function requires multiple interventions and the standardization of the different stages of islet transplant process. This article will review the possible areas of intervention and the ongoing research toward this important goal.


Arris & Gale lecture. Regulation and responses of gallbladder muscle activity in health and disease.
A complex relationship links biliary symptoms with the mechanisms of gallbladder emptying and the presence of gallstones. This relationship has been investigated by clinical studies of symptoms associated with gallstones, by investigation of gallbladder emptying and cholecystokinin (CCK) release in patients with gallstones, and after cholecystectomy, or truncal vagotomy, and in the irritable bowel syndrome (IBS). Laboratory studies examined receptor density on bovine gallbladder, and contractility of human gallbladder in response to a variety of stimuli was studied in vitro. A set of six symptoms associated with the presence of gallstones was identified; IBS appeared to be present in two-fifths of patients before cholecystectomy but only one-third of these patients had persistent IBS symptoms one year after operation. Gallbladder emptying studies confirmed the poor contraction of stone-bearing gallbladders; abnormal patterns of emptying were also found in patients with IBS. Gallbladder emptying and filling appear to be largely neurally regulated. CCK receptor density was very low in gallbladder tissue, suggesting that receptors on nerve cells might mediate the action of CCK. Relaxation of gallbladder muscle was mediated by adrenergic and nitrergic nerves. The inflammatory mediator bradykinin, however, had a strong direct action on muscle cells to cause gallbladder contraction. The work reported here gives an overview of the symptoms and mechanisms of disease associated with the presence of stones in the gallbladder.


Patient-reported outcomes 12 months after hepatitis C treatment with direct-acting antivirals: Results from the PROP UP study.
The long-term impact of hepatitis C virus (HCV) therapy with all-oral direct-acting antivirals (DAAs) on patient-reported outcomes (PROs) has not been well-described. We characterized changes in PROs from pre-treatment to 12 months post-treatment in a real-world cohort. PROP UP was a multi-centre observational cohort study of 1601 patients treated with DAAs at 11 US gastroenterology/hepatology practices from 2015 to 2017. PROs were evaluated pre-treatment (T1) and 12 months post-treatment (T5). A minimally important change (MIC) threshold was prespecified as >5% change in PRO scores from T1 to T5. Multivariable analyses identified predictors of change. Three-quarters of patients were 55 or older; 45% were female, 60% were white, 33% were black, nearly half had cirrhosis. The most commonly-prescribed DAA regimens were sofosbuvir-based (83%) and grazoprevir/elbasvir (11%). Study retention was >95%. On average, small improvements were observed at 3 months post-treatment in all PROs and sustained at 12 months post-treatment among patients with sustained virologic response (SVR). Clinically meaningful improvements were achieved in fatigue (mean change score: -3.7 [-4.2, -3.1]), sleep (mean change score: -3.1 [-3.7, -2.5]), abdominal pain (mean change score: -2.6 [-3.3, -1.9]) and functional well-being (mean change score: -7.0 [-6.0, -8.0]). Symptom improvements were generally not sustained with no SVR (n = 52). Patients with cirrhosis and MELD ≥12 had the greatest improvements in functional well-being (-12.9 [-17.6, -8.1]). The improvements in patient-reported outcomes reported by patients who achieved SVR following HCV DAA therapy were durable at 12 months post-treatment.


Need for Cross-Validation of Single Particle Cryo-EM.
Cross-validation is used to determine the validity of a model on unseen data by assessing if the model is overfitted to noise. It is widely used in many fields, from artificial intelligence to structural biology in X-ray crystallography and nuclear magnetic resonance. Although there are concerns of map overfitting in cryo-electron microscopy (cryo-EM), cross-validation is rarely used. The problem is that establishing a performance metric of the maps over unseen data (given by 2D-projection images) is difficult due to the low signal-to-noise ratios in the individual particles. Here, I present recent advances for cryo-EM map reconstruction. I highlight that the gold-standard procedure can fail to detect map overfitting in certain cases, showing the necessity of assessing the map quality on unbiased data. Finally, I describe the challenges and advantages of developing a robust cross-validation methodology for cryo-EM.


Epidemiological analysis of take-all decline in winter wheat.
Take-all dynamics within crops differing in cropping history (the number of previous consecutive wheat crops) were analyzed using an epidemiological model to determine the processes affected during take-all decline. The model includes terms for primary infection, secondary infection, inoculum decay, and root growth. The average rates of root production did not vary with cropping history. The force of primary infection increased from a low level in 1st wheat crops, to a maximum in 2nd to 4th wheat crops, and then to intermediate levels thereafter. The force of secondary infection was low but increased steadily during the season in first wheat crops, was delayed but rose and fell sharply in 2nd to 4th wheat crops, and for 5th and 7th wheat crops returned to similar dynamics as that for 1st wheat crops. Chemical seed treatment with silthiofam had no consistent effect on the take-all decline process. We conjecture that these results are consistent with (i) low levels of particulate inoculum prior to the first wheat crop leading to low levels of primary infection, low levels of secondary infection, and little disease suppression; (ii) net amplification of inoculum during the first wheat crop and intercrop period; (iii) increased levels of primary and secondary infection in subsequent crops, but higher levels of disease suppression; and (iv) an equilibrium between the pathogen and antagonist populations by the 5th wheat, reflected by lower overall rates of primary infection, secondary infection, disease suppression and hence, disease severity.


Feasibility of laparoscopic pyloromyotomy under spinal anesthesia.
Most agents used for GA are considered to be neurotoxins and affect developing brains in experimental models, leading to a push for spinal anesthesia (SA). There are no reports of laparoscopic pyloromyotomy (LP) performed under SA. We present our experience with LP and SA and discuss feasibility. A retrospective analysis was performed on a consecutive series of patients who underwent an LP. An 'intent to treat' analysis was utilized, and GA was compared to SA. Data regarding patient characteristics, operative intervention, complications, and postoperative course were collected. Twelve cases had attempted SA for the LP, 9 were successful. During the same time, 12 cases underwent LP under GA. We found no difference for length of procedure, time to the first feed, or the postoperative LOS. The time to leave the OR after conclusion of the procedure was significantly shorter for the SA group (14min vs. 28min, p<0.001). There were no complications from the SA, however three cases had to be converted to GA. It is feasible and safe to perform laparoscopic pyloromyotomy under spinal anesthesia. Given the increasing concern over the use of GA in infants, consideration may be given to use of SA for LP.


Anti-inflammatory activity of standardized dichloromethane extract of Salvia connivens on macrophages stimulated by LPS.
A previous study demonstrated that the chloroform extract of Salvia connivens Epling (Lamiaceae) has anti-inflammatory activity. Identification of the active components in the dicholorometane extract (DESC), and, standardization of the extract based in ursolic acid. DESC was prepared by percolation with dichlromethane and after washed with hot hexane, its composition was determined by CG-MS and NMR, and standardized by HPLC. The anti-inflammatory activity was tested on acute TPA-induced mouse ear oedema at doses of 2.0 mg/ear. The cell viability of macrophages was evaluated by MTT method, and pro- and anti-inflammatory interleukin levels were measured using an ELISA kit. Ursolic acid, oleanolic acid, dihydroursolic acid and eupatorin were identified in DESC, which was standardized based on the ursolic acid concentration (126 mg/g). The anti-inflammatory activities of DESC, the acid mixture, and eupatorin (2 mg/ear) were 60.55, 57.20 and 56.40% inhibition, respectively, on TPA-induced ear oedema. The IC50 of DESC on macrophages was 149.4 μg/mL. DESC (25 μg/mL) significantly reduced TNF-α (2.0-fold), IL-1β (2.2-fold) and IL-6 (2.0-fold) in macrophages stimulated with LPS and increased the production of IL-10 (1.9-fold). Inflammation is a basic response to injuries, and macrophages are involved in triggering inflammation. Macrophage cells exhibit a response to LPS, inducing inflammatory mediators, and DESC inhibits the biosynthesis of the pro-inflammatory and promote anti-inflammatory cytokines. DESC has an anti-inflammatory effect; reduced the levels of IL-1β, Il-6 and TNF-α; and increases IL-10 in macrophages stimulated with LPS. Ursolic acid is a good phytochemical marker.


The function of the human interferon-beta 1a glycan determined in vivo.
Recombinant human interferon-beta (rhIFN-beta) is the leading therapeutic intervention shown to change the cause of relapsing-remitting multiple sclerosis, and both a nonglycosylated and a significantly more active glycosylated variant of rhIFN-beta are used in treatment. This study investigates the function of the rhIFN-beta1a glycan moiety and its individual carbohydrate residues, using the myxovirus resistance (Mx) mRNA as a biomarker in Mx-congenic mice. We showed that the Mx mRNA level in blood leukocytes peaked 3 h after s.c. administration of rhIFN-beta1a. In addition, a clear dose-response relationship was confirmed, and the Mx response was shown to be receptor-mediated. Using specific glycosidases, different glycosylation analogs of rhIFN-beta1a were obtained, and their activities were determined. The glycosylated rhIFN-beta1a showed significantly higher activity than its deglycosylated counterpart, due to a protein stabilization/solubilization effect of the glycan. It is interesting to note that the terminating sialic acids were essential for these effects. Conclusively, the structure/bioactivity relationship of rhIFN-beta1a was determined in vivo, and it provided a novel insight into the role of the rhIFN-beta1a glycan and its carbohydrate residues. The possibilities of improving the pharmacological properties of rhIFN-beta1a using glycoengineering are discussed.


The coevolution of sexual imprinting by males and females.
Sexual imprinting is the learning of a mate preference by direct observation of the phenotype of another member of the population. Sexual imprinting can be paternal, maternal, or oblique if individuals learn to prefer the phenotypes of their fathers, mothers, or other members of the population, respectively. Which phenotypes are learned can affect trait evolution and speciation rates. "Good genes" models of polygynous systems predict that females should evolve to imprint on their fathers, because paternal imprinting helps females to choose mates that will produce offspring that are both viable and sexy. Sexual imprinting by males has been observed in nature, but a theory for the evolution of sexual imprinting by males does not exist. We developed a good genes model to study the conditions under which sexual imprinting by males or by both sexes can evolve and to ask which sexual imprinting strategies maximize the fitness of the choosy sex. We found that when only males imprint, maternal imprinting is the most advantageous strategy. When both sexes imprint, it is most advantageous for both sexes to use paternal imprinting. Previous theory suggests that, in a given population, either males or females but not both will evolve choosiness in mating. We show how environmental change can lead to the evolution of sexual imprinting behavior by both sexes in the same population.


Effect of adding ketorolac to intravenous morphine patient-controlled analgesia on bowel function in colorectal surgery patients--a prospective, randomized, double-blind study.
Postoperative ileus (PI) is the transient impairment of bowel motility due to surgical trauma and the associated physiological responses. Postoperative ileus results in patient discomfort, increases gastrointestinal risks, prolongs hospital stay and increases medical expenses. In this study, we investigated the effect of patient-controlled analgesia (PCA) morphine with or without ketorolac on bowel functions in patients after colorectal surgeries. A total of 79 patients who received elective colorectal resection were randomly allocated into two groups receiving either intravenous PCA morphine (M group) or intravenous PCA morphine plus ketorolac (K group). Recovery of bowel functions (bowel movement, passage of flatus, and soft diet intake), pain scores, morphine consumption, time for first ambulation, and opioid-related side-effects were recorded. Patients in the K group received 29% less morphine than patients in the M group with comparable pain scores. The first bowel movement (1.5 [0.7-1.9] vs. 1.7 [1.0-2.8] days, P < 0.05) and the first ambulation (2.2 +/- 1.0 vs. 2.8 +/- 1.2 days, P < 0.05) were significantly earlier in the K group than in the M group. The time of the first flatus passing, the first intake of soft diet, and duration of hospital stay were not significantly different between the two groups. The results of this study suggest that addition of ketorolac to intravenous morphine PCA provides an opioid-sparing effect but has limited benefit in shortening the duration of bowel immobility and time to first ambulation. These findings imply that postoperative ileus is attributable to multiple factors in addition to morphine consumption.


Differential perturbation of intersubunit and interdomain communications by glycine 141 mutation in Escherichia coli CRP.
Upon binding of cAMP, concomitant changes in CRP structure across the subunit and domain interfaces are observed. In order to identify the structural elements involved in the coupling of interfacial interactions, structural perturbation was introduced at residue 141 by site-directed mutagenesis. Thermodynamic parameters defining protein stability, cAMP binding, and subunit assembly of the mutant were determined. Conformational changes probed by proteolytic digestion and fluorescence signal reported by the fluorescein-labeled C178 lead to a dissection of the contribution of the intersubunit and interdomain interactions, respectively, in the cAMP-modulated DNA binding of CRP. In the absence of cAMP, mutant G141Q is sensitive to protease attack at the subunit interface, an established property of wild type CRP observed only in the presence of cAMP. Although the G141Q mutant assumes a subunit alignment similar to that of the activated CRP, this mutant absolutely requires cyclic nucleotide for specific DNA interaction. Monitoring the fluorescence probe attached to the C-terminal DNA binding domain of the G141Q mutant showed that the DNA binding domain responds quantitatively to the binding of cyclic nucleotide to the N-terminal domain. This result suggests that domain reorientation is a required structural change in addition to subunit alignment. In summary, mutation at G141 has differentially perturbed the communication network which involves the interfacial interactions between subunits and domains. The G141Q CRP mutant assumes a conformation that partially resembles the active form represented by the observed subunit realignment, but complete activation of the mutant requires binding of cyclic nucleotide which induces the reorientation of domains. Furthermore, the G --> Q mutation leads to a loss in the discriminatory power of CRP for only cAMP. Other cyclic nucleotides are capable of activating this mutant.


Do Tele-Operators Learn to Better Judge Whether a Robot Can Pass Through an Aperture?
This experiment examined whether tele-operators learn to better judge a robot's ability to pass through an aperture, hereafter referred to as pass-ability judgments, and detailed the nature of such learning. Jones, Johnson, and Schmidlin reported that tele-operators' pass-ability judgments did not improve over the course of their experiment, which was surprising. In each of seven blocks, tele-operators made pass-ability judgments about 10 apertures whose width varied. During each trial, participants drove the robot toward the aperture, answered yes or no to whether it could pass through that aperture, and then attempted to drive the robot through the aperture. Pass-ability judgments were analyzed in terms of percentage correct and absolute thresholds; the latter mimicked how Jones et al. analyzed their data. Learning was revealed when judgments were analyzed in terms of percentage correct and not when analyzed in terms of absolute thresholds. Further analyses revealed that tele-operators only improved their pass-ability judgments for impassable apertures, and tele-operators' perceptual sensitivity and response bias changed over the course of the experiment. The percentage correct-based analyses revealed that tele-operators learned to make better pass-ability judgments. Jones et al.'s decision to analyze their data in terms of absolute thresholds obscured learning. The present results suggested that researchers should employ percentage correct when studying learning in this domain, training protocols should focus on improving tele-operators' abilities to judge the pass-ability of impassable apertures, and tele-operators truly learned to better discriminate passable and impassable apertures.


Exploring the genetic diversity of the Japanese population: Insights from a large-scale whole genome sequencing analysis.
The Japanese archipelago is a terminal location for human migration, and the contemporary Japanese people represent a unique population whose genomic diversity has been shaped by multiple migrations from Eurasia. We analyzed the genomic characteristics that define the genetic makeup of the modern Japanese population from a population genetics perspective from the genomic data of 9,287 samples obtained by high-coverage whole-genome sequencing (WGS) by the National Center Biobank Network. The dataset comprised populations from the Ryukyu Islands and other parts of the Japanese archipelago (Hondo). The Hondo population underwent two episodes of population decline during the Jomon period, corresponding to the Late Neolithic, and the Edo period, corresponding to the Early Modern era, while the Ryukyu population experienced a population decline during the shell midden period of the Late Neolithic in this region. Haplotype analysis suggested increased allele frequencies for genes related to alcohol and fatty acid metabolism, which were reported as loci that had experienced positive natural selection. Two genes related to alcohol metabolism were found to be 12,500 years out of phase with the time when they began to increase in the allele frequency; this finding indicates that the genomic diversity of Japanese people has been shaped by events closely related to agriculture and food production.


[Uridine diphosphate sugar in meningiomas of the brain].
The content of uridine-diphosphate (UDP)-saccharides, such as UDP-glucose (UDPG) and UDP-N-acetylglucosamine (UDPAG) was examined in the meningiomas obtained at surgery. Typical, atypical, and anaplastic meningiomas were used. Biochemical data were compared with histological findings. The total level of UDP-saccharides (UDPG + UDPAG) in the meningiomas was demonstrated not to depend on the grade of anaplasia. A positive correlation was found between the UDPG/UDPAG ratio was from 1.73 in typical (benign) neoplasms to 6 or even higher in meningiomas with severe sings of malignancy (anaplastic meningiomas). The UDPG/UDPAG ratio seems to reflect the nature and rate of tumor growth.


Return to Oz: voice pitch facilitates assessments of men's body size.
Listeners associate low voice pitch (fundamental frequency and/or harmonics) and formants (vocal-tract resonances) with large body size. Although formants reliably predict size within sexes, pitch does not reliably predict size in groups of same-sex adults. Voice pitch has therefore long been hypothesized to confound within-sex size assessment. Here we performed a knockout test of this hypothesis using whispered and 3-formant sine-wave speech devoid of pitch. Listeners estimated the relative size of men with above-chance accuracy from voiced, whispered, and sine-wave speech. Critically, although men's pitch and physical height were unrelated, the accuracy of listeners' size assessments increased in the presence rather than absence of pitch. Size assessments based on relatively low pitch yielded particularly high accuracy (70%-80%). Results of Experiment 2 revealed that amplitude, noise, and signal degradation of unvoiced speech could not explain this effect; listeners readily perceived formant shifts in manipulated whispered speech. Rather, in Experiment 3, we show that the denser harmonic spectrum provided by low pitch allowed for better resolution of formants, aiding formant-based size assessment. These findings demonstrate that pitch does not confuse body size assessment as has been previously suggested, but instead facilitates accurate size assessment by providing a carrier signal for vocal-tract resonances.


Management of obstructive sleep apnea in Europe.
In Europe, the services provided for the investigation and management of obstructive sleep apnoea (OSA) varies from country to country. The aim of this questionnaire-based study was to investigate the current status of diagnostic pathways and therapeutic approaches applied in the treatment of OSA in Europe, qualification requirements of physicians involved in diagnosis and treatment of OSA, and reimbursement of these services. Two questionnaires were sent to 39 physicians in 22 countries in Europe. In order to standardize the responses, the questionnaire was accompanied by an example. Sleep centers from 21 countries (38 physicians) participated. A broad consistency among countries with respect to the following was found: pathways included referral to sleep physicians/sleep laboratories, necessity for objective diagnosis (primarily by polysomnography), use of polygraphic methods, analysis of polysomnography (PSG), indications for positive airway pressure (PAP) therapy, application of standard continuous PAP (CPAP) therapy (100% with an CPAP/APAP ratio of 2.24:1), and the need (90.5%) and management of follow-up. Differences were apparent in reimbursement of the diagnostic procedures and follow-up, in the procedures for PAP titration from home APAP titration with portable sleep apnea monitoring (38.1%) up to hospital monitoring with PSG and APAP (85.7%), and in the qualification requirements of sleep physicians. Management of OSA in different European countries is similar except for reimbursement rules, qualification of sleep specialists and procedures for titration of the CPAP treatment. A European network (such as the one accomplished by the European Cooperation in Science and Technology [COST] B26 Action) could be helpful for implementing these findings into health-service research in order to standardize management in a cost effective perspective.


Exercise protects cardiac mitochondria against ischemia-reperfusion injury.
Three to five consecutive days of endurance exercise can protect the heart against an ischemia-reperfusion (IR) insult. However, the mechanisms responsible for this exercise-mediated cardioprotection remain unknown. Given the important role that mitochondria play in IR-induced cardiac myocyte injury, we hypothesized that exercise training promotes cardioprotection, at least in part, by increasing mitochondrial antioxidants, preventing mitochondrial release of reactive oxygen species, and protecting cardiac mitochondria against IR-induced oxidative damage and functional impairment. To test our hypothesis, Sprague-Dawley rats were assigned to either sedentary (n = 16) or exercise-trained (n = 16) groups. Exercise-trained animals performed 5 d of treadmill running for 60 min·d(-1) at 30 m·s(-1). Hearts were excised from sedentary and exercised-trained animals and were either perfused for 80 min or exposed to 40 min of global ischemia followed by 45 min of reperfusion by using an ex vivo isolated working heart model. After the protocol, cardiac subsarcolemmal and intermyofibrillar mitochondria were isolated and used to determine respiratory control ratio, reactive oxygen species emission, and indices of oxidative stress and apoptosis. Our results support our hypothesis because exercise training protected both cardiac subsarcolemmal and intermyofibrillar mitochondria from IR-induced uncoupling and oxidative damage. Specifically, the levels of cardiac mitochondrial 4-hydroxynonenal-conjugated proteins were elevated in hearts from sedentary animals exposed to IR compared with cardiac mitochondria isolated from exercise-trained animals. Exercise also resulted in an increase in mitochondrial antioxidant enzymes (copper-zinc superoxide dismutase, manganese superoxide dismutase, and glutathione peroxidase) and prevented the IR-induced release of proapoptotic proteins from the mitochondria. Collectively, these novel findings reveal that exercise-induced cardioprotection is mediated, at least in part, through mitochondrial adaptations resulting in a mitochondrial phenotype that resists IR-induced damage.


Detecting Traces of Prehistoric Human Migrations by Geographic Synthetic Maps of Polyomavirus JC.
The polyomavirus JC (JCV) is a double-stranded DNA virus that is ubiquitous in human populations and is excreted in urine by a large percentage of individuals (20-70%). The strong genetic stability, combined with a mechanism of transmission mainly within the family, makes JCV a good marker of human migrations. In this study, the coevolution of JCV with its human host is investigated by using over a thousand nucleotide sequences deposited in the EMBL database; they correspond to the IG region, which is the genomic region with the highest rate of variation. The pattern of genetic diversity in JCV is evaluated by the principal coordinates analysis and the construction of synthetic maps. The first principal coordinate supports the existence of two distinct virus lineages, both arising from the ancestral African type. The first synthetic map suggests a two-migration model of the human dispersal out of Africa, thus implying a more complex picture than that known from human genes. The second principal coordinate points out the distinctiveness of strains coming from Asian/Amerind populations. The picture yielded by the second synthetic map appears to be more consistent with that known from human genes. In fact, it provides evidence of a deep split of the Asian lineage of JCV into two main branches: one diffusing in Japan and Americas, the other in Southeast Asia. The view that JCV, with its peculiar feature of a dual early emergence from Africa, can provide new information about the evolutionary history of our ancestors is discussed.


The rate of structural change: the confocal scanning laser ophthalmoscopy ancillary study to the ocular hypertension treatment study.
To compare rates of topographic change in ocular hypertensive eyes that develop primary open-angle glaucoma (POAG) compared to eyes that do not, and to identify factors that influence the rate of change. Longitudinal, randomized clinical trial. Four hundred forty-one participants (832 eyes) in the Confocal Scanning Laser Ophthalmoscopy Ancillary Study to the Ocular Hypertension Treatment Study were included. POAG was defined as repeatable visual field, photography-based optic disc changes, or both. The rate of topographic change in the 52 participants (66 eyes) who developed POAG was compared with that of participants who did not develop POAG using multivariable mixed effects models. In both univariate and multivariate analyses, the rate of rim area loss was significantly faster in eyes in which POAG developed than in eyes in which it did not (univariate mean, -0.0131 mm(2)/year and -0.0026 mm(2)/year, respectively). The significantly faster rate of rim area loss in black persons found in the univariate analysis did not remain significant when baseline disc area was included in the model. In multivariate analyses, the rate of rim area loss and other topographic parameters also was significantly faster in eyes with worse baseline visual field pattern standard deviation and higher intraocular pressure during follow-up. Moreover, a significant rate of rim area loss was detected in eyes in which POAG did not develop (P < .0001). The rate of rim area loss in eyes with an optic disc POAG endpoint was significantly faster than in those with a visual field POAG endpoint. The rate of rim area loss is approximately 5 times faster in eyes in which POAG developed compared with eyes in which it did not. These results suggest that measuring the rate of structural change can provide important information for the clinical management of ocular hypertensive patients. Additional follow-up is needed to determine whether the statistically significant change in the eyes in which POAG did not develop represents normal aging or glaucomatous change not detected by conventional methods.


Outcomes in non-ST-segment elevation myocardial infarction complicated by in-hospital cardiac arrest based on management strategy.
There are limited data on in-hospital cardiac arrest (IHCA) complicating non-ST-segment-elevation myocardial infarction (NSTEMI) based on management strategy. We used National Inpatient Sample (2000-2017) to identify adults with NSTEMI (not undergoing coronary artery bypass grafting) and concomitant IHCA. The cohort was stratified based on use of early (hospital day 0) or delayed (≥hospital day 1) coronary angiography (CAG), percutaneous coronary intervention (PCI), and medical management. Outcomes included incidence of IHCA, in-hospital mortality, adverse events, length of stay, and hospitalization costs. Of 6,583,662 NSTEMI admissions, 375,873 (5.7 %) underwent early CAG, 1,133,143 (17.2 %) received delayed CAG, 2,326,391 (35.3 %) underwent PCI, and 2,748,255 (41.7 %) admissions were managed medically. The medical management cohort was older, predominantly female, and with higher comorbidities. Overall, 63,085 (1.0 %) admissions had IHCA, and incidence of IHCA was highest in the medical management group (1.4 % vs 1.1 % vs 0.7 % vs 0.6 %, p < 0.001) compared to early CAG, delayed CAG and PCI groups, respectively. In adjusted analysis, early CAG (adjusted OR [aOR] 0.67 [95 % confidence interval {CI} 0.65-0.69]; p < 0.001), delayed CAG (aOR 0.49 [95 % CI 0.48-0.50]; p < 0.001), and PCI (aOR 0.42 [95 % CI 0.41-0.43]; p < 0.001) were associated with lower incidence of IHCA compared to medical management. Compared to medical management, early CAG (adjusted OR 0.53, CI: 0.49-0.58), delayed CAG (adjusted OR 0.34, CI: 0.32-0.36) and PCI (adjusted OR 0.19, CI: 0.18-0.20) were associated with lower in-hospital mortality (all p < 0.001). Early CAG and PCI in NSTEMI was associated with lower incidence of IHCA and lower mortality among NSTEMI-IHCA admissions.


Gene alterations identified by expression profiling in tumor-associated endothelial cells from invasive ovarian carcinoma.
Therapeutic strategies based on antiangiogenic approaches are beginning to show great promise in clinical studies. However, full realization of these approaches requires identification of key differences in gene expression between endothelial cells from tumors versus their normal counterparts. Here, we examined gene expression differences in purified endothelial cells from 10 invasive epithelial ovarian cancers and 5 normal ovaries using Affymetrix U133 Plus 2.0 microarrays. More than 400 differentially expressed genes were identified in tumor-associated endothelial cells. We selected and validated 23 genes that were overexpressed by 3.6- to 168-fold using real-time reverse transcription-PCR and/or immunohistochemistry. Among these, the polycomb group protein enhancer of Zeste homologue 2 (EZH2), the Notch ligand Jagged1, and PTK2 were elevated 3- to 4.3-fold in tumor-associated endothelial cells. Silencing these genes individually with small interfering RNA blocked endothelial cell migration and tube formation in vitro. The present study shows that tumor and normal endothelium differ at the molecular level, which may have significant implications for the development of antiangiogenic therapies.


Cutting edge: circulating plasmablasts induce the differentiation of human T follicular helper cells via IL-6 production.
B cells require CD4(+) T follicular helper (Tfh) cells to progress through the germinal center and provide protective Ab responses. In this article, we reveal a reciprocal interaction whereby circulating human plasmablasts are potent inducers of the Tfh cell-differentiation program, including the expression of their key transcription factor Bcl-6. The markedly increased propensity of plasmablasts, compared with naive B cells, to induce Tfh cell differentiation was due to their increased production of IL-6. Specific targeting of IL-6 using tocilizumab therapy in patients with rheumatoid arthritis led to a significant reduction in circulating Tfh cell numbers and IL-21 production, which was correlated with reduced plasmablast formation. Our data uncover a positive-feedback loop between circulating plasmablasts and Tfh cells that could sustain autoimmunity and spread Ab-driven inflammation to unaffected sites; this represents an important therapeutic target, as well as reveals a novel mechanism of action for tocilizumab.


Synthesis and expression in Escherichia coli of a gene for kappa-bungarotoxin.
A gene which codes for the 66-residue polypeptide of kappa-bungarotoxin has been chemically synthesized by linking together 3 synthetic double-stranded oligonucleotides in a bacterial plasmid. The synthesis incorporated six unique silent restriction sites spaced throughout the gene for use in cassette mutagenesis. Direct expression of the kappa-bungarotoxin polypeptide by itself in Escherichia coli failed to result in a stable product. The toxin polypeptide was stabilized and expressed in E. coli as part of a fusion protein with rat intestinal fatty acid binding protein under control of the nalidixic acid inducible recA promoter. Two fusion protein constructs were prepared that differed only in the cleavage site between the fatty acid binding protein and the toxin polypeptide. One contained a factor Xa cleavage site, and the other, since the toxin itself is devoid of methionine, contained a methionyl residue that served as a cyanogen bromide cleavage site. The fusion proteins were isolated by ion-exchange chromatography and reverse-phase HPLC. The construct containing the factor Xa cleavage site could not be cleaved under nondenaturing conditions. On the other hand, kappa-bungarotoxin was efficiently cleaved from the methionyl fusion protein with CNBr. The toxin polypeptide was isolated by reverse-phase HPLC and ion-exchange chromatography and produced a complete and specific blockade of neuronal nicotinic acetylcholine receptors in chick ciliary ganglia which was indistinguishable from that produced by a comparable amount of venom-purified kappa-bungarotoxin.


Cardiovascular mediation of clonidine-induced ultrasound production in infant rats.
In infant rats, administration of the alpha2 adrenoceptor agonist clonidine simultaneously evokes ultrasound production and bradycardia. In this study the authors examined in 8-day-old rats whether these 2 responses to clonidine are causally related. In Experiment 1 pups were pretreated with saline or prenalterol (0.1 or 1.0 mg/kg), a beta1 adrenoceptor agonist that increases cardiac rate, followed by administration of clonidine (1.0 mg/kg). Prenalterol pretreatment suppressed clonidine-induced ultrasound production at both doses. Prenalterol also increased skin temperature, however, suggesting that suppression of ultrasound was modulated in part by increased body temperature. Consistent with this suggestion, in Experiment 2 mild hyperthermia significantly inhibited clonidine-induced ultrasound production. Finally, in Experiment 3 the authors found that the pretreatments used in Experiments 1 and 2 prevent or dampen the effects of clonidine on cardiac rate. These results suggest that clonidine's effect on ultrasound production is mediated by its effects on the cardiovascular system.


Reactions to clinical reinterpretation of a gene variant by participants in a sequencing study.
PurposeAs genome science advances, people receiving personalized genetic information may receive reinterpretations of pathogenicity. Little is known about responses to adjusted results. We examined how reinterpretations might affect attitudes about genetic testing and intentions to share results with family.MethodsData were collected from high-socioeconomic-status participants (n = 58) in a genome sequencing study. Twenty-nine originally learned they were carriers of Duarte variant galactosemia, based on a variant that was reclassified as benign. Positive testers (n = 19) had a newly identified causative variant and remained carriers. Negative testers (n = 10) learned they were no longer carriers. Twenty-nine controls were carriers for a disease of comparable severity with no reclassification. Participants completed baseline, immediate, and 3-month follow-up surveys.ResultsApproximately 80% of participants demonstrated complete or partially accurate recall of their results and reported positive or neutral reactions to their result and about genetic information more generally. Positive testers reported lower intentions to share the change in their result with family. Controls reported the lowest intentions to learn future results. There were no significant group differences or changes over time in perceived ambiguity or negative emotions.ConclusionThe results suggest that high-socioeconomic-status participants understand reinterpretations conferring a neutral change or a change from carrier to noncarrier status. Participants' responses to changes in carrier results for a low-risk condition indicated minimal adverse effects.


Using structured and unstructured data to identify patients' need for services that address the social determinants of health.
Increasingly, health care providers are adopting population health management approaches that address the social determinants of health (SDH). However, effectively identifying patients needing services that address a SDH in primary care settings is challenging. The purpose of the current study is to explore how various data sources can identify adult primary care patients that are in need of services that address SDH. A cross-sectional study described patients in need of SDH services offered by a safety-net hospital's federally qualified health center clinics. SDH services of social work, behavioral health, nutrition counseling, respiratory therapy, financial planning, medical-legal partnership assistance, patient navigation, and pharmacist consultation were offered on a co-located basis and were identified using structured billing and scheduling data, and unstructured electronic health record data. We report the prevalence of the eight different SDH service needs and the patient characteristics associated with service need. Moreover, characteristics of patients with SDH services need documented in structured data sources were compared with those documented by unstructured data sources. More than half (53%) of patients needed SDH services. Those in need of such services tended to be female, older, more medically complex, and higher utilizers of services. Structured and unstructured data sources exhibited poor agreement on patient SDH services need. Patients with SDH services need documented by unstructured data tended to be more complex. The need for SDH services among a safety-net population is high. Identifying patients in need of such services requires multiple data sources with structured and unstructured data.


Ascidian tail formation requires caudal function.
Although the tail is one of the major characteristics of animals of the phylum Chordata, evolutionary aspects of the molecular mechanisms involved in its formation are not clear. To obtain insights into these issues, we have isolated and investigated the caudal gene of an ascidian, one of the lower animal groups among chordates. Ascidian caudal is expressed from the midgastrula stage onward in the lateral walls of the posterior neural tube cell lineage and also in the posterior epidermal cells from the neurula stage. Thus, ascidian caudal expression is restricted to the ectoderm of a tail-forming region throughout embryogenesis. Suppression of caudal function by an antisense oligonucleotide or a dominant negative construct caused inhibition of the cell movement required for tail formation. Overexpression of wild-type caudal mRNA in an ascidian animal cap, an animal half explant prepared at the eight-cell stage, caused elongation of the cap. Furthermore, Xenopus embryos injected with dominant negative ascidian caudal exhibited defects in elongation, suggesting a conserved caudal function among chordates. These results indicate that caudal function is required for chordate tail formation and may play a key role in its evolution.


Awake Craniotomy with Cortical and Subcortical Speech Mapping for Supramarginal Cavernoma Resection.
Awake craniotomy allows mapping of eloquent brain regions and monitoring neurocognitive functioning intraoperatively to maximize extent of resection and minimize cognitive morbidity.1,2 During resection of cavernous malformations in eloquent areas, intraoperative cognitive monitoring can also allow for safer maximal excision of the hemosiderin ring, which is correlated with improved seizure-free outcome.3,4 We present the case of a 33-year-old right-handed male with a new-onset seizure who presented to his local emergency department after experiencing visual hallucinations before losing consciousness. Computed tomography scan of the head revealed a calcified lesion in the left temporal/parietal area. Presurgical workup revealed left hemispheric language dominance and language activation within the overlying supramarginal gyrus representing phonologic working memory on functional magnetic resonance imaging.5 Diffusion tensor imaging identified the arcuate fasciculus and lateral portion of the superior longitudinal fasciculus to be intimately associated with the deep margin of the lesion.6 After consent was obtained, we performed an awake craniotomy and resection of the lesion through a transsulcal approach, with eloquent cortical mapping using a novel high-density circular grid,7,8 as well as subcortical stimulation/mapping and continuous intraoperative cognitive monitoring using multiple language paradigms; the patient was baselined on these paradigms preoperatively (Video 1). Several phonologic/paraphasic errors were made during resection of the hemosiderin ring, likely related to mechanical manipulation. The patient was discharged to home on postoperative day 4 with outpatient speech therapy for speech hesitancy. At 1-week postoperative testing, language skills were considered within normal limits.


Do perfume additives termed human pheromones warrant being termed pheromones?
Two studies of the effects of perfume additives, termed human pheromones by the authors, have conveyed the message that these substances can promote an increase in human sociosexual behaviour [Physiol. Behav. 75 (2003) R1; Arch. Sex. Behav. 27 (1998) R2]. The present paper presents an extended analysis of this data. It is shown that in neither study is there a statistically significant increase in any of the sociosexual behaviours for the experimental groups. In the control groups of both studies, there are, however, moderate but statistically significant decreases in the corresponding behaviour. Most notably, there is no support in data for the claim that the substances increase the attractiveness of the wearers of the substances to the other sex. It is concluded that more research using matched homogenous groups of participants is needed.


Foetal development of skeletal muscle in bovines as a function of maternal nutrition, foetal sex and gestational age.
To determine the effects of maternal nutrition on modifications of foetal development of the skeletal muscle and possible increase in the potential of skeletal muscle growth in cattle, gestating cows were either fed 190% NRC recommendations (overnourished; ON) or 100% NRC recommendation (control; CO). Interaction between maternal nutrition (MN) and the foetal sex (FS) was also investigated. Foetuses were necropsied at four different time points throughout gestation (139, 199, 241 and 268 days of gestation) to assess the mRNA expression of myogenic, adipogenic and fibrogenic markers in skeletal muscle. Phenotypic indicators of the development of skeletal muscle fibres, intramuscular lipogenesis and collagen development were also evaluated. Modifications in mRNA expression of skeletal muscle of foetuses were observed in function of MN and FS despite the lack of effect of MN and FS on foetal weight at necropsy. Maternal ON increased the mRNA expression of the myogenic marker Cadherin-associated protein, beta 1 (CTNNB1) and adipogenic markers Peroxissome proliferator-activated receptor gamma (PPARG) and Zinc finger protein 423 (ZNF423) at midgestation. However, no differences on foetal skeletal muscle development were observed between treatments at late gestation indicating that a compensatory development may have occurred on CO foetuses making the effect of MN on skeletal muscle development not significant at late gestation. Moreover, our data have shown an evidence of sexual dimorphism during foetal stage with a greater skeletal muscle development in male than in female foetuses. In conclusion, providing a higher nutritional level to pregnant cows changes the trajectory of the development of skeletal muscle during midgestation, but apparently does not change the potential of post-natal growth of muscle mass of the offspring, as no differences in skeletal muscle development were observed in late gestation.


Two-state conformational changes in inositol 1,4,5-trisphosphate receptor regulated by calcium.
Inositol 1,4,5-trisphosphate receptor (IP3R) is a highly controlled calcium (Ca2+) channel gated by inositol 1,4,5-trisphosphate (IP3). Multiple regulators modulate IP3-triggered pore opening by binding to discrete allosteric sites within IP3R. Accordingly we have postulated that these regulators structurally control ligand gating behavior; however, no structural evidence has been available. Here we show that Ca2+, the most pivotal regulator, induced marked structural changes in the tetrameric IP3R purified from mouse cerebella. Electron microscopy of the IP3R particles revealed two distinct structures with 4-fold symmetry: a windmill structure and a square structure. Ca2+ reversibly promoted a transition from the square to the windmill with relocations of four peripheral IP3-binding domains, assigned by binding to heparin-gold. Ca2+-dependent susceptibilities to limited digestion strongly support the notion that these alterations exist. Thus, Ca2+ appeared to regulate IP3 gating activity through the rearrangement of functional domains.


Status report on education in the economics of animal health: results from a European survey.
Education on the use of economics applied to animal health (EAH) has been offered since the 1980s. However, it has never been institutionalized within veterinary curricula, and there is no systematic information on current teaching and education activities in Europe. Nevertheless, the need for economic skills in animal health has never been greater. Economics can add value to disease impact assessments; improve understanding of people's incentives to participate in animal health measures; and help refine resource allocation for public animal health budgets. The use of economics should improve animal health decision making. An online questionnaire was conducted in European countries to assess current and future needs and expectations of people using EAH. The main conclusion from the survey is that education in economics appears to be offered inconsistently in Europe, and information about the availability of training opportunities in this field is scarce. There is a lack of harmonization of EAH education and significant gaps exist in the veterinary curricula of many countries. Depending on whether respondents belonged to educational institutions, public bodies, or private organizations, they expressed concerns regarding the limited education on decision making and impact assessment for animal diseases or on the use of economics for general management. Both public and private organizations recognized the increasing importance of EAH in the future. This should motivate the development of teaching methods and materials that aim at developing the understanding of animal health problems for the benefit of students and professional veterinarians.


Mode of action of the hemin-controlled inhibitor of protein synthesis: studies with factors from rabbit reticulocytes.
Previously [de Haro, C., Datta, A & Ochoa, S. (1978) Proc. Natl. Acad. Sci. USA 75, 243--247] it was shown with initiation factors from Artemia salina embryos that the activity of the initiator methionyl-tRNA binding factor eIF-2 is stimulated by another factor (ESP, for eIF-2 stimulating protein) present, like eIF-2, in ribosomal salt washes. Incubation of eIF-2 with translational inhibitor from rabit reticulocytes, in the presence of ATP, abolished the ESP effect. At physiological concentrations eIF-2 was virtually inactive without ESP. These observations indicated that the translational inhibitor acts by converting eIF-2 to a form that is not stimulated by ESP. The same observations have now been made with eIF-2 and ESP from rabbit reticulocytes but, in this case, the dependence of eIF-2 activity on ESP is much more pronounced than with the A. salina factors. eIF-2 from reticulocytes interacts with ESP from A. salina and conversely.


ERG3-Encoding Sterol C5,6-DESATURASE in Candida albicans Is Required for Virulence in an Enterically Infected Invasive Candidiasis Mouse Model.
Gastrointestinal colonization by Candida species is considered the main source of candidemia. The ERG3 gene in Candida albicans encodes a sterol C5,6-desaturase, which is essential for ergosterol biosynthesis. Although ERG3 inactivation shows reduced virulence in mouse models of disseminated candidiasis, the role of ERG3 in intestinal infections is unknown. Here, we infected mice with the C. albicans strains CAE3DU3 and CAF2-1, containing mutant and wild-type ERG3, respectively, and studied gut infection and colonization by these strains. We found that the CAE3DU3 strain showed reduced colonization, pathogenesis, damage to gut mucosa, and chemokine production in the mouse model of invasive candidiasis. Additionally, mice inoculated with CAE3DU3 showed lower mortality than mice inoculated with CAF2-1 (p < 0.0001). Chemokines were less induced in the gut inoculated with CAE3DU3 than in the gut inoculated with CAF2-1. Histopathologically, although the wild-type gene was associated with a higher pathogenicity and invasion of the gut mucosa and liver tissues causing remarkable tissue necrosis, the erg3/erg3 mutant was associated with a higher accumulation of cells and lower damage to surrounding tissues than wild-type ERG3. These results establish that the ergosterol biosynthetic pathway may be associated with C. albicans gut colonization and subsequent dissemination.


Inhibition of c-Jun N-terminal kinase enhances temozolomide-induced cytotoxicity in human glioma cells.
Previous studies have revealed that p38, a member of the family of stress-activated protein kinases (SAPKs), cooperates with the Chk1-pathway to bring about temozolomide (TMZ)-induced G2 arrest, and that the inhibition of either pathway alone is sufficient to sensitize U87MG glioma cells to TMZ-induced cytotoxicity. c-Jun N-terminal kinase (JNK), another SAPK, has been reported to have several roles of cell survival, oncogenesis, growth, differentiation and cell death. To elucidate the functions of JNK in glioma cells treated with TMZ, we analyzed alterations in JNK and the effect of modification of JNK in U87MG human glioma cells treated with TMZ. We found that JNK was phosphorylated 1-2 days after TMZ treatment and that pretreatment (for 24 h) and post-treatment (for 72 h) with a JNK inhibitor SP600125 at a concentration of 200 nM or higher remarkably reduced clonogenicity in the TMZ-treated cells. The phosphorylation of the JNK target protein c-Jun, but not of ATF-2, was inhibited by this concentration of SP600125. Therefore JNK was proved to have a role of survival in glioma cells treated with TMZ, and c-Jun-related responses were suggested to be more important in the JNK-mediated survival of glioma cells with DNA damage. SP600125 amplified the percentage of senescence-like cells and of mitotic catastrophe cells in TMZ-treated U87MG and U87MG-E6 cells, respectively, suggesting that the enhancement of TMZ-induced cytotoxicity by a JNK inhibitor in glioma cells is induced (at least in part) by the potentiation of cell death pathways induced by TMZ alone. Further investigation based on the present data may provide a viable approach for enhancing TMZ-induced cytotoxicity in human gliomas.


SC3: consensus clustering of single-cell RNA-seq data.
Single-cell RNA-seq enables the quantitative characterization of cell types based on global transcriptome profiles. We present single-cell consensus clustering (SC3), a user-friendly tool for unsupervised clustering, which achieves high accuracy and robustness by combining multiple clustering solutions through a consensus approach (http://bioconductor.org/packages/SC3). We demonstrate that SC3 is capable of identifying subclones from the transcriptomes of neoplastic cells collected from patients.


Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern.
The medical community relies on clinical expertise and published guidelines to assist physicians with choices in empirical therapy for system-based infectious syndromes, such as community-acquired pneumonia and urinary-tract infections (UTIs). From the late 1990s, multidrug-resistant Enterobacteriaceae (mostly Escherichia coli) that produce extended-spectrum beta lactamases (ESBLs), such as the CTX-M enzymes, have emerged within the community setting as an important cause of UTIs. Recent reports have also described ESBL-producing E coli as a cause of bloodstream infections associated with these community-onset UTIs. The carbapenems are widely regarded as the drugs of choice for the treatment of severe infections caused by ESBL-producing Enterobacteriaceae, although comparative clinical trials are scarce. Thus, more rapid diagnostic testing of ESBL-producing bacteria and the possible modification of guidelines for community-onset bacteraemia associated with UTIs are required.


Effect of Intralesional Steroid Injections Among Patients with Acquired Laryngotracheal Stenosis Undergoing Endoscopic Balloon Dilation Using Pulmonary Function Tests.
Objectives: Laryngotracheal stenosis (LTS) is characterized by an abnormal decrease in the upper airway diameter. The pulmonary function test (PFT) is an effective adjunctive diagnostic tool for upper airway obstruction. LTS can be managed with either open surgery or less invasive endoscopic approaches, among which endoscopic balloon dilation is the main method; this may include concurrent intralesional steroid injection (ILSI), which has the potential of improving the outcomes. However, the effectiveness of ILSI is unclear. We aimed to compare the improvement in PFT parameters among patients with acquired LTS following endoscopic balloon dilation who received and did not receive ILSIs. We also compared the recurrence times and rates between the 2 patient cohorts. Methods: We retrospectively collected data regarding pre- and postoperative PFTs, as well as inter-dilation interval records, obtained between June 2015 and April 2020. Results: We included 34 patients with acquired etiologies. The most common cause of stenosis was intubation (52.9%), followed by trauma (29.4%). Further, 52.9% of the patients received ILSIs. Symptom recurrence was reported in 23 (67.6%) cases, with no significant between-group difference -0.1389 [95% confidence interval (CI): -0.4483, 0.1705]. The mean (standard deviation) duration of the first reintervention was 8.62 (8.00) and 7.38 (3.20) months among patients who did and did not receive ILSIs, respectively (mean difference -1.23, P = .614, 95% CI -6.30, 3.84). Conclusion: Our findings indicated that PFT parameters improved following endoscopic balloon dilation, with forced expiratory volume in 1 second being significantly higher with concurrent ILSI. However, there was no between-method difference in the treatment effectiveness. Additionally, the restenosis recurrence rate was consistent with that reported in the literature.


Effects of lowering average of below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy. LIPID Trial Research Group.
Cholesterol lowering in patients with above-average cholesterol levels has been shown to reduce the progression of atherosclerosis and lower the risk of coronary heart disease events. However, there has been uncertainty about the effects of cholesterol lowering in patients with average or below-average cholesterol levels. In this study, 522 patients with a history of myocardial infarction or unstable angina and with baseline levels of total cholesterol between 4 and 7 mmol/L (mean, 5.7 mmol/L) were randomized to treatment with a low fat diet plus pravastatin (40 mg daily) or to a low fat diet plus placebo. Treatment with pravastatin reduced the levels of total cholesterol by 19%, LDL cholesterol by 27%, apolipoprotein B by 19%, and triglycerides by 13% (all 2P<.0001) and increased apolipoprotein A1 and HDL cholesterol levels by 4% (both 2P<.0005), in comparison with placebo. Carotid atherosclerosis was assessed from B-mode ultrasound measurements of the common carotid artery. After 4 years, mean carotid wall thickness had increased by 0.048 mm (SE=0.01) in the placebo group and declined by 0.014 mm in the pravastatin-treated group (SE=0.01) (2P for difference <.0001). The effect of treatment on wall thickness was similar in three groups classified by tertiles of total cholesterol at baseline, with mean levels of 4.8, 5.7, and 6.6 mmol/L, respectively (2P for interaction >.8). Treatment with pravastatin reduced the development of carotid atherosclerosis among patients with coronary heart disease and a wide range of pretreatment cholesterol levels. Treatment with this agent prevented any detectable increase in carotid wall thickening over 4 years of follow-up.


Sperm tail flexibility test: a simple test for selecting viable spermatozoa for intracytoplasmic sperm injection from semen samples without motile spermatozoa.
The objective was to describe the results of the injection of immotile spermatozoa with flexible tails when only immotile spermatozoa are present in the semen sample. A retrospective study was conducted to analyze the procedure results for 10 couples who participated in our intracytoplasmic sperm injection program. The sperm tail was considered flexible when it moved up and down independently of the head movement, and it was considered inflexible when the movement occurred together (tail plus head). The fertilization and pregnancy rate were analyzed. The normal fertilization rate (presence of 2 pronuclei) was 30.3% (40/132), and the abnormal fertilization rate (presence of less than or more than 2 pronuclei) was 6.81% (9/132). A total of 52 embryos were obtained with 9 transfer procedures performed (pregnancy rate: 11.12%). The sperm tail flexibility test (STFT) is an easy and cost-effective way for selecting viable immotile spermatozoa and can be used as an alternative method for determining the viability of spermatozoa. This test seems to be a simple and risk-free method when compared to the swelling test.


[Construction and analysis of muscle functional network for exoskeleton robot].
Exoskeleton nursing robot is a typical human-machine co-drive system. To full play the subjective control and action orientation of human, it is necessary to comprehensively analyze exoskeleton wearer's surface electromyography (EMG) in the process of moving patients, especially identifying the spatial distribution and internal relationship of the EMG information. Aiming at the location of electrodes and internal relation between EMG channels, the complex muscle system at the upper limb was abstracted as a muscle functional network. Firstly, the correlation characteristics were analyzed among EMG channels of the upper limb using the mutual information method, so that the muscle function network was established. Secondly, by calculating the characteristic index of network node, the features of muscle function network were analyzed for different movements. Finally, the node contraction method was applied to determine the key muscle group that reflected the intention of wearer's movement, and the characteristics of muscle function network were analyzed in each stage of moving patients. Experimental results showed that the location of the myoelectric collection could be determined quickly and efficiently, and also various stages of the moving process could effectively be distinguished using the muscle functional network with the key muscle groups. This study provides new ideas and methods to decode the relationship between neural controls of upper limb and physical motion.


Fabrication of Color Glass with High Light Transmittance by Pearlescent Pigments and Optical Adhesive.
In this study, we propose a solution process for realizing colored glass for building integrated photovoltaic (BIPV) systems by spin coating a color solution composed of pearlescent pigments mixed in a Norland Optical Adhesive (NOA) matrix. Color solutions are made from mixing pearlescent pigments in NOA63. Compared to a physical vapor deposition process, color coatings are achieved by spin coating in a relatively simple and inexpensive process at room temperature. The optical properties can be easily controlled by adjusting the spin coating speed and the concentration of the pearlescent pigments. The produced colored glass achieved a high transmittance of 85% or more in the visible wavelength range, except for the wavelength spectrum exhibiting the maximum reflectance. In addition, we propose a one-step lamination process of colored glass on a solar cell by leveraging on the adhesive property of the NOA matrix. This eliminates the cost and process of additional ethylene vinyl acetate (EVA) layer or other materials used in the conventional lamination process. The colored glass produced through this study has stability that does not change its properties over time. Therefore, it is expected to be applied to the BIPV solar module market where aesthetics and energy efficiency are required.


Non-destructive measurement technique for water content in organic solvents based on a thermal approach.
The water content of organic solvents is one of the crucial properties that affect the quality of the products and the efficiency of the manufacturing processes. The established water determination methods such as Karl Fischer titration and gas chromatography require skilled operators, specific reagents, and prolonged measurement time. Thus, they are not suitable for both on-line and in-line applications. In this study, we aim to develop a real-time and low-cost device with reliable accuracy. The proposed device based on a newly developed thermal approach could non-destructively detect the water content in multiple organic solvents at low concentrations with high accuracy and without the use of any specific reagent. Experiments were performed for the determination of water content in organic solvents such as methanol, ethanol, and isopropanol. The results show that the proposed device is feasible for the water content determination in methanol, ethanol, and isopropanol at 0-1% w/w. A Bland-Altman plot to illustrate the differences in measurements between the proposed device and coulometric Karl Fischer titration shows that most of the measurements lie within the limits of agreement where 95% of the differences between the two methods are expected to fall in the range of -0.13% and 0.09%.


Absolute and convective instabilities of a film flow down a vertical fiber subjected to a radial electric field.
We consider the motion of a gravity-driven flow down a vertical fiber subjected to a radial electric field. This flow exhibits rich dynamics including the formation of droplets, or beads, driven by a Rayleigh-Plateau mechanism modified by the presence of gravity as well as the Maxwell stress at the interface. A spatiotemporal stability analysis is performed to investigate the effect of electric field on the absolute-convective instability (AI-CI) characteristics. We performed a numerical simulation on the nonlinear evolution of the film to examine the transition from CI to AI regime. The numerical results are in excellent agreement with the spatiotemporal stability analysis. The blowup behavior of nonlinear simulation predicts the formation of touchdown singularity of the interface due to the effect of electric field. We try to connect the blowup behavior with the AI-CI characteristics. It is found that the singularities mainly occur in the AI regime. The results indicate that the film may have a tendency to form very sharp tips due to the enhancement of the absolute instability induced by the electric field. We perform a theoretical analysis to study the behaviors of the singularities. The results show that there exists a self-similarity between the temporal and spatial distances from the singularities.


Prevalence and Antimicrobial Susceptibility of Enterobacteriaceae Isolated from Retail Pepper in Vietnam.
To investigate the microbial quality of retail pepper in Vietnam, the enumeration and detection of Enterobacteriaceae and the screening of cefotaxime (CTX)-resistant coliforms were performed by using 84 commercial samples. Although Enterobacteriaceae were isolated from 78 samples, the number of Enterobacteriaceae was lower than 1.0 log CFU/g in 46 samples. For the detection of Enterobacteriaceae with the International Organization for Standardization methods, Salmonella spp., Escherichia coli, Klebsiella pneumoniae, Cronobacter sakazakii, and Enterobacter cloacae complex were isolated from 5, 12, 36, 19, and 30 samples, respectively. During screening of CTX-resistant coliforms, K. pneumoniae, C. sakazakii, and E. cloacae complex were isolated from 8, 1, and 21 samples, respectively. Seven K. pneumoniae and seven E. cloacae complex isolates obtained in the screening of CTX-resistant coliforms were resistant to at least one of the three third-generation cephalosporins (CTX, ceftazidime, and cefpodoxime). Moreover, one E. cloacae complex cluster IV and all K. pneumoniae isolates were positive for extended-spectrum β-lactamase genes or plasmid-mediated AmpC β-lactamase genes or both. Additionally, two extended-spectrum β-lactamase-producing K. pneumoniae isolates and one AmpC β-lactamase-producing E. cloacae complex cluster IV isolate were positive for the plasmid-mediated quinolone resistance determinants and also had amino acid alterations in the quinolone resistance-determining regions of GyrA and ParC. Furthermore, 10 E. cloacae complex isolates were positive for the plasmid-mediated fosfomycin resistance gene fosA. As pepper is often consumed without a heating process, the possible spread to humans of foodborne, opportunistic, and nosocomial infection pathogens or resistance genes from foods prepared or seasoned with pepper cannot be excluded. Therefore, it is necessary to handle pepper by using hygienic conditions during the cultivation, harvesting and processing steps.


Serious injuries secondary to cardiopulmonary resuscitation: incidence and associated factors.
To determine the incidence of serious rib cage damage (SRD) and serious visceral damage (SVD) secondary to cardiopulmonary resuscitation (CPR) and to explore associated factors. We analyzed data from the prospective registry of cases of sudden death in Tarragona, Spain (the ReCaPTa study). Cases were collected from multiple surveillance sources. In this study we included the cases of autopsied nonsurvivors after attempted manual CPR between April 2014 and May 2016. A specific protocol to detect injuries secondary to CPR was used during the autopsies. We analyzed 109 cases. The mean age at death was 63 years and 32.1% were women. SRD were found in 63.3% and SVD in 14.7%. The group with SRD were significantly older (63 vs 59 years, P=.031) and included higher percentages of persons with a chest circumference over 101 cm (56.5 vs 30%, P=.016) and a waist circumference over 100 cm (62.3 vs 37.5%, P=.017). A multivariable analysis confirmed chest circumference over 101 cm as the only risk factor for SRD (odds ratio [OR], 2.45; 95% CI, 1.03-5.84) and female sex as the only risk factor for SVD (OR, 5.02; 95% CI, 1.18-21.25). Women and any patient with a chest circumference greater than 101 cm are at greater risk for serious injuries related to CPR.


The effect of visitor number and spice provisioning in pacing expression by jaguars evaluated through a case study.
Captive animals exhibit stereotypic pacing in response to multiple causes, including the inability to escape from human contact. Environmental enrichment techniques can minimize pacing expression. By using an individual-based approach, we addressed whether the amount of time two males and a female jaguar (Panthera onca) devote to pacing varied with the number of visitors and tested the effectiveness of cinnamon and black pepper in reducing pacing. The amount of time that all jaguars engaged in pacing increased significantly with the number of visitors. Despite the difference between the males regarding age and housing conditions, both devoted significantly less time to pacing following the addition of both spices, which indicates their suitability as enrichment techniques. Mean time devoted to pacing among the treatments did not differ for the female. Our findings pointed out to the validity of individual-based approaches, as they can reveal how suitable olfactory stimuli are to minimizing stereotypies irrespective of particular traits.


Formation and hematopoietic differentiation of human embryoid bodies by suspension and hanging drop cultures.
The in vitro aggregation of human embryonic stem cells (hESCs) into clusters termed embryoid bodies (EBs) allows for the spontaneous differentiation of cells representing endoderm, mesoderm, and ectoderm lineages. This stochastic process results however, in the generation of low numbers of differentiated cells, and can be enhanced to some extent by the addition of exogenous growth factors or overexpression of regulatory genes. In the authors' laboratory, the use of hematopoietic cytokines in combination with the mesoderm inducer bone morphogenetic protein-4 (BMP-4) was able to generate up to 90% of CD45(+) hematopoietic cells with colony-forming unit (CFU) activity. This unit describes two protocols that have been successfully applied in the authors' laboratory for the generation of EBs in (1) suspension and (2) hanging drop (HD) cultures from enzymatically digested clumps of undifferentiated hESC colonies.


Evolutionary relationships of Metazoa within the eukaryotes based on molecular data from Porifera.
Recent molecular data provide strong support for the view that all metazoan phyla, including Porifera, are of monophyletic origin. The relationship of Metazoa, including the Porifera, to Plantae, Fungi and unicellular eukaryotes has only rarely been studied by using cDNAs coding for proteins. Sequence data from rDNA suggested a relationship of Porifera to unicellular eukaryotes (choanoflagellates). However, ultrastructural studies of choanocytes did not support these findings. In the present study, we compared amino acid sequences that are found in a variety of metazoans (including sponges) with those of Plantae, Fungi and unicellular eukaryotes, to obtain an answer to this question. We used the four sequences from 70 kDa heat-shock proteins, the serine-threonine kinase domain found in protein kinases, beta-tubulin and calmodulin. The latter two sequences were deduced from cDNAs, isolated from the sponge Geodia cydonium for the phylogenetic analyses presented. These revealed that the sponge molecules were grouped into the same branch as the Metazoa, which is statistically (significantly) separated from those branches that comprise the sequences from Fungi, Plantae and unicellular eukaryotes. From our molecular data it seems evident that the unicellular eukaryotes existed at an earlier stage of evolution, and the Plantae and especially the Fungi and the Metazoa only appeared later.


Biomarkers for evaluation of prostate cancer prognosis.
Prostate cancer, with a lifetime prevalence of one in six men, is the second cause of malignancy-related death and the most prevalent cancer in men in many countries. Nowadays, prostate cancer diagnosis is often based on the use of biomarkers, especially prostate-specific antigen (PSA) which can result in enhanced detection at earlier stage and decreasing in the number of metastatic patients. However, because of the low specificity of PSA, unnecessary biopsies and mistaken diagnoses frequently occur. Prostate cancer has various features so prognosis following diagnosis is greatly variable. There is a requirement for new prognostic biomarkers, particularly to differentiate between inactive and aggressive forms of disease, to improve clinical management of prostate cancer. Research continues into finding additional markers that may allow this goal to be attained. We here selected a group of candidate biomarkers including PSA, PSA velocity, percentage free PSA, TGFβ1, AMACR, chromogranin A, IL-6, IGFBPs, PSCA, biomarkers related to cell cycle regulation, apoptosis, PTEN, androgen receptor, cellular adhesion and angiogenesis, and also prognostic biomarkers with Genomic tests for discussion. This provides an outline of biomarkers that are presently of prognostic interest in prostate cancer investigation.


Developmental outcomes at one and two years of children conceived by intracytoplasmic sperm injection.
Present opinions regarding developmental delay of children conceived with intracytoplasmic sperm injection (ICSI) are variable and without consensus. We compared developmental outcome at 1 and 2 years of 50 children conceived by ICSI with 51 spontaneously conceived children. Assessments were performed using the Bayley Scales of Infant Development for motor and mental development and quality of behavior, and the CARE-Index for the quality of parent-child interaction. No difference was present in the motor and mental development of study and control groups, as assessed by the Bayley Scales. However, 1-year-old ICSI children had lower Behavioral Index scores than controls in the "Motor Quality" item (p = 0.04). Regarding interaction with parents, ICSI families had lower "father cooperation" CARE-Index scores (p = 0.02) and lower sensitivity scores (p = 0.007). No significant differences were present between study and control groups for the 2-year-old children. ICSI conceived children develop normally. When assessed by the Bayley Scales of Infant Development and the CARE-Index, the differences in quality of development and social interaction observed at 1 year of age had no negative effect on the overall level of development, and appeared to be related to developmental processes of the entire family unit rather than to ICSI-related biological effects. Observed differences dissipated with familial adaptation and were not observed at 2 years of age.


Comparison of inpatient distribution amongst different medical alliances in a county: a longitudinal study on a healthcare reform in rural China.
China has launched the medical alliances (MAs) reform to drive the development of primary medical institutions and decrease health inequality in rural areas. Three different types of MAs were built to promote township hospitals in Y County. This study aims to evaluate the actual effect of China's MAs reform in rural areas on inpatient distribution especially amongst different types of MAs. We obtain 2008-2015 claims data from the New Cooperative Medical Scheme (NCMS) in Y County, Hubei Province of China. We consider January 2008-December 2010 as the pre-reform period and January 2011-December 2015 as the post-reform period. We use independent sample t-test and single-group interrupted time series analysis (ITSA) to compare the number of inpatients per month in the three MAs, including three county and 10 township hospitals before and after the reform. We use paired t-test and multiple-group ITSA between seven township hospitals within MAs and seven township hospitals outside MAs. The MAs reform in Y County increased the number of inpatients in county and township hospitals within MAs. After the reform, the number of inpatients per month in county hospitals had an upward trend, with a slope of 31.01 person/month (P < 0.000). Approximately 19.99 new inpatients were admitted to township hospitals monthly after the reform (P < 0.000). Furthermore, township hospitals within MAs had a substantial increase in the number of inpatients (10.45 new inpatients monthly) compared with those outside MAs. The MAs reform in Y County significantly improved the capability of medical institutions within MAs. After the reform, township hospitals within MAs had greater development advantages than those outside MAs. However, it also caused further imbalance in the county region, which contained the new health inequality risk.


Gesture and speech integration: an exploratory study of a man with aphasia.
In order to comprehend fully a speaker's intention in everyday communication, information is integrated from multiple sources, including gesture and speech. There are no published studies that have explored the impact of aphasia on iconic co-speech gesture and speech integration. To explore the impact of aphasia on co-speech gesture and speech integration in one participant with aphasia and 20 age-matched control participants. The participant with aphasia and 20 control participants watched video vignettes of people producing 21 verb phrases in three different conditions, verbal only (V), gesture only (G), and verbal gesture combined (VG). Participants were required to select a corresponding picture from one of four alternatives: integration target, a verbal-only match, a gesture-only match, and an unrelated foil. The probability of choosing the integration target in the VG that goes beyond what is expected from the probabilities of choosing the integration target in V and G was referred to as multi-modal gain (MMG). The participant with aphasia obtained a significantly lower multi-modal gain score than the control participants (p<0.05). Error analysis indicated that in speech and gesture integration tasks, the participant with aphasia relied on gesture in order to decode the message, whereas the control participants relied on speech in order to decode the message. Further analysis of the speech-only and gesture-only tasks indicated that the participant with aphasia had intact gesture comprehension but impaired spoken word comprehension. The results confirm findings by Records ( 1994 ) that reported that impaired verbal comprehension leads to a greater reliance on gesture to decode messages. Moreover, multi-modal integration of information from speech and iconic gesture can be impaired in aphasia. The findings highlight the need for further exploration of the impact of aphasia on gesture and speech integration.


Developmental modularity and phenotypic novelty within a biphasic life cycle: morphogenesis of a cone snail venom gland.
The venom gland of predatory cone snails (Conus spp.), which secretes neurotoxic peptides that rapidly immobilize prey, is a proposed key innovation for facilitating the extraordinary feeding behaviour of these gastropod molluscs. Nevertheless, the unusual morphology of this gland has generated controversy about its evolutionary origin and possible homologues in other gastropods. I cultured feeding larvae of Conus lividus and cut serial histological sections through the developing foregut during larval and metamorphic stages to examine the development of the venom gland. Results support the hypothesis of homology between the venom gland and the mid-oesophageal gland of other gastropods. They also suggest that the mid-region of the gastropod foregut, like the anterior region, is divisible into dorsal and ventral developmental modules that have different morphological, functional and ontogenetic fates. In larvae of C. lividus, the ventral module of the middle foregut transformed into the anatomically novel venom gland of the post-metamorphic stage by rapidly pinching-off from the main dorsal channel of the mid-oesophagus, an epithelial remodelling process that may be similar to other cases where epithelial tubes and vesicles arise from a pre-existing epithelial sheet. The developmental remodelling mechanism could have facilitated an abrupt evolutionary transition to the derived morphology of this important gastropod feeding innovation.


Identification of two domains of the p70 Ku protein mediating dimerization with p80 and DNA binding.
The Ku autoantigen is a heterodimer of 70 (p70) and approximately 80 kDa (p80) subunits that is the DNA-binding component of the DNA-dependent protein kinase (DNA-PK) complex involved in DNA repair and V(D)J recombination. Binding to DNA ends is critical to the function of DNA-PK, but how Ku interacts with DNA is not completely understood. To define the role of p70 and p80 and their dimerization in DNA binding, heterodimers were assembled by co-expressing the subunits using recombinant baculoviruses. Two p70 dimerization sites, amino acids 1-115 and 430-482, respectively, were identified. Binding of p70 to linear double-stranded DNA could be demonstrated by an immunoprecipitation assay, and required the C-terminal portion (amino acids 430-609), but not interaction with p80. The p70 mutants 1-600, 1-542, 1-115, and 430-600 did not bind DNA efficiently. However, DNA binding of 1-600, 1-542, and 1-115, but not 430-600, was restored by dimerization with p80, indicating that p70 has two DNA binding sites, each partially overlapping one of the dimerization sites. The C-terminal domain can bind DNA by itself, but the N-terminal domain requires dimerization with p80. These observations could be relevant to the multiple functional activities of Ku and explain controversies regarding the role of dimerization in DNA binding.


Changing resistance to antimicrobial drugs, and resistance typing in clinically significant strains of Staphylococcus epidermidis.
Resistance to 11 antimicrobial drugs was assessed in 532 clinically significant strains of Staphylococcus epidermidis received in the years 1978, 1979 and 1980 and compared with that of strains collected in 1976 and 1977 for an international study. Only 14% of strains were sensitive to all the drugs tested. Resistance to gentamicin increased significantly from 7% to 33% during the study period. The degree of association between pairs of drugs was assessed. There was strong association between resistance to methicillin, aminoglycosides and macrolide antibiotics and only weak association between resistance to novobiocin, tetracycline, chloramphenicol and penicillin. Patterns of resistance were complex and may be useful as an accessory typing system.


Chronic granulomatous disease in a 23-year-old female.
A 23-year-old girl with clinical and laboratory findings characteristic of chronic granulomatous disease is described. The patient was admitted to hospital because of severe disseminated aspergillosis. Studies of neutrophils showed normal phagocytosis but impaired microbicidal killing and a failure of the respiratory burst activity as measured by NBT-reduction, superoxide generation, chemiluminescence and antibody-dependent cell mediated cytotoxicity. Patient's neutrophils had normal chemotactic responsiveness but a marked impairment in the level of serum chemotactic activity was observed. Neutrophils from the parents and 2 maternal aunts showed normal values for all the determinations. The lack of evidence for a carrier state in all the family members studied together with the inability to detect a mixed population of neutrophils in our patient are in contrast with the Lyon's hypothesis of X-chromosome inactivation. Our findings suggest an autosomal recessive inheritance in this female with chronic granulomatous disease.


Questionnaire-based survey conducted in 2011 concerning endoscopic management of Barrett's esophagus in East Asian countries.
Endoscopic definitions and management of Barrett's esophagus vary widely among countries. To examine the current situation regarding diagnosis, epidemiology, management and treatment of Barrett's esophagus in East Asian countries using a questionnaire-based survey. Representative members of the Committee of the International Gastrointestinal Consensus Symposium developed and sent a questionnaire to major institutions in China, South Korea, Japan, Thailand, Indonesia, and the Philippines. A total of 56 institutions in the 6 countries participated in the survey. We found that the presence of specialized columnar metaplasia is considered to be important for diagnosing Barrett's esophagus in East Asian countries except for Japan. C&M criteria have not been well accepted in East Asia. The palisade vessels are mainly used as a landmark for the esophagogastric junction in Japan. The prevalence of long segment Barrett's esophagus is extremely low in East Asia, while the prevalence of short segment Barrett's esophagus is very high only in Japan, likely due to different diagnostic criteria. Among East Asian countries, we found both similarities and differences regarding diagnosis and management of Barrett's esophagus. The findings in the present survey are helpful to understand the current situation of Barrett's esophagus in East Asian countries.


Genetic profiling differentiates second primary tumors from metastases in adult metachronous soft tissue sarcoma.
Purpose. Patients with soft tissue sarcomas (STS) are at increased risk of second primary malignancies, including a second STS, but distinction between metastases and a second primary STS is difficult. Patients and Methods. Array-based comparative genomic hybridization (aCGH) was applied to 30 multiple STS of the extremities and the trunk wall from 13 patients. Different histotypes were present with malignant fibrous histiocytomas/undifferentiated pleomorphic sarcomas being the predominant subtype. Results. aCGH profiling revealed genetic complexity with multiple gains and losses in all tumors. In an unsupervised hierarchical cluster analysis, similar genomic profiles and close clustering between the first and subsequent STS were identified in 5 cases, suggesting metastatic disease, whereas the tumors from the remaining 8 patients did not cluster and showed only weak pairwise correlation, suggesting development of second primary STS. Discussion. The similarities and dissimilarities identified in the first and second STS suggest that genetic profiles can be used to distinguish soft tissue metastases from second primary STS. The demonstration of genetically different soft tissue sarcomas in the same patient suggests independent tumor origin and serves as a reminder to consider development of second primary STS, which has prognostic and therapeutic implications.


[High-risk eating behavior in Mexican adolescents. Data on the student population in the Federal District].
Data of the Drug and Alcohol Prevalence in Student Population of Mexico City Survey 1997 were used to achieve knowledge about the presence of risk eating behaviors, characteristic of eating disorders in the student population of Mexico city (N = 10,173). The sample was conformed by boys (47.9%) and girls (52.1%), with a mean age of 14.5 years (SD = 1.8). The identification of the differences between boys and girls, and age groups in two occurrence categories of risk eating behavior (ever and two or more times per week) were among the main objectives. An eleven items scale with three answering options about eating behavior during the last three months was used. The BMI-P distributed normally, with greater percentage of overweight, than underweight in both sexes. A greater percentage of risk eating behaviors were found among girls, excluding hard exercising and binge eating, as well as similar percentages of laxative and enema use in both sexes. The analysis held by age groups for risk eating behaviors showed significant differences in binge eating, self induced vomiting, pills and enemas use among boys, while girls showed differences in almost all of these practices, being the group of 18 and 19 years where the greater percentages were found.