Effect of an orally applied herbal immunomodulator on cytokine induction and antibody response in normal and immunosuppressed mice.
The influence of the oral administration of a herbal immunomodulator, consisting of an aqueous-ethanolic extract of the mixed herbal drugs Thujae summitates, Baptisiae tinctoriae radix, Echinaceae purpureae radix and Echinaceae pallidae radix, on cytokine induction and antibody response against sheep red blood cells was investigated in mice. The treatment of the animals with the extract caused no enhancement of the cytokine titers in the serum. Spleen cells isolated from the treated mice, however, produced higher amounts of IL-2, IFNgamma and GM-CSF ex vivo in comparison to spleen cells isolated from control animals, especially after additional stimulation by lipopolysaccharides or concanavalin A. The application of the extract also triggered the production of IL-1 and TNFalpha by peritoneal macrophages ex vivo. The influence of the herbal extract on the antibody response was examined by the plaque forming cell assay. The administration of the extract caused a significant enhancement of the antibody response against sheep red blood cells, inducing an increase in the numbers of splenic plaque forming cells and the titers of specific antibodies in the sera of the treated animals. In mice, immunosuppressed by old age or additional treatment with hydrocortisone, the therapy with the extract resulted in a normalization of the antibody response against sheep red blood cells.


The relationship between negative peer relationship and non-suicidal self-injury in Chinese adolescents: A moderated-mediation model.
The objective of the study was to investigate the mediating effect of regulatory emotional self-efficacy (RESE) between negative peer relationship and non-suicidal self-injury (NSSI), as well as the moderating effect of gender difference. A study of 578 Chinese adolescents (46.9% males, mean age = 16.32 years, SD =0.54) was conducted using the Child and Adolescent Peer Relationship Inventory, Regulatory Emotional Self-Efficacy Scale, and the Adolescent Self-Injury Questionnaire. Negative peer relationship was positively correlated with NSSI, and RESE was negatively correlated with negative peer relationship and NSSI. RESE mediated the association between negative peer relationship and NSSI. The first stage(predicting the effect of negative peer relationship on RESE) and the second stage (predicting the effect of RESE on NSSI) of the mediation effect of RESE were both moderated by gender. Specifically, compared with boys, the effect of negative peer relationship on RESE was stronger for girls, and the effect of RESE on NSSI was stronger for girls than boys. Negative peer relationships may influence NSSI of adolescents through the mediating effect of RESE and the moderating role of gender.


Is EAT-10 Useful to Assess Swallowing during the Chemo-Radiotherapy Phase in Patients with Head and Neck Cancer? A Pilot Study.
The 10-item Eating-Assessment Tool (EAT-10) is a dysphagia screening test. In HNC patients, screening and diagnosis of dysphagia are not well-established. To determine the metrological properties of the EAT-10 compared with videofluoroscopy in non-surgical HNC-patients and to assess the relationship between EAT-10 scores and patients' self-reported symptoms. Prospective cohort study. Forty-six HNC-patients recently diagnosed and referred to chemoradiotherapy (CRT). Main outcome was evidence of dysphagia according to EAT-10 score, self-perception on a Visual Analog Scale (VAS) of impaired swallowing, severity on the Penetration-Aspiration Scale (PAS), and the Functional Oral Intake Scale (FOIS). Patients were assessed at baseline, before-CRT, after-CRT, and at 3-month follow-up. A strong baseline correlation between EAT-10, VAS, and FOIS was observed. All 3 values decreased in weeks 6 to 9 after CRT initiation; a poor correlation of EAT-10 with VAS was observed at 3-month follow-up. A receiver operating characteristic curve determined new cut-off points (sensitivity/specificity) for safe swallowing: baseline 3 (86%, 77%); post-CRT, 15 (62.5%, 80%); and 3-month follow-up, 4 (83%, 75%). New safe-swallow EAT-10-points are suggested for this population during screening and the oncological follow-up. A poor correlation between EAT10-score and patient self-reported symptoms was observed at the end-RT and at 3-month follow-up, highlighting the need for an objective evaluation instrument.


Predicting later language outcomes from the Language Use Inventory.
To examine the predictive validity of the Language Use Inventory (LUI), a parent report of language use by children 18-47 months old (O'Neill, 2009). 348 children whose parents had completed the LUI were reassessed at 5-6 years old with standardized, norm-referenced language measures and parent report of developmental history. The relationship between scores on the LUI and later measures was examined through correlation, binary classification, and receiver operating characteristic curve analysis. For children aged 24-47 months at the time of LUI completion, LUI scores correlated significantly with language measure scores. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were also calculated for 4 cutoff scores on the LUI, including -1.64 SD, a score that maximized sensitivity to 81% and specificity to 93%. For children aged 18-23 months at the time of LUI completion, specificity and NPV were high, but sensitivity and PPV were lower than desirable. The results provide initial support for the LUI's predictive validity, particularly for children 24-47 months, and suggest the LUI can serve as an indicator of later language outcomes in referred populations. The results compare favorably to findings for other early child-language measures.


Fast determination of four polar contaminants in soy nutraceutical products by liquid chromatography coupled to tandem mass spectrometry.
An analytical method based on a modified QuPPe (quick polar pesticide) extraction procedure coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was evaluated for the determination of four polar compounds (chlorate, fosetyl-Al, maleic hydrazide, and perchlorate) in nutraceutical products obtained from soy. Experimental conditions including extraction such as solvent, acidification, time, and clean-up sorbents were varied. Acidified acetonitrile (1 % formic acid, v/v) was used as extraction solvent instead of methanol (conventional QuPPe), which provides a doughy mixture which cannot be injected into the LC. Clean-up or derivatization steps were avoided. For analysis, several stationary phases were evaluated and Hypercarb (porous graphitic carbon) provided the best results. The optimized method was validated and recoveries ranged between 46 and 119 %, and correction factors can be used for quantification purposes bearing in mind that inter-day precision was equal to or lower than 17 %. Limits of quantification (LOQs) ranged from 4 to 100 μg kg-1. Soy-based nutraceutical products were analyzed and chlorate was detected in five samples at concentrations between 63 and 1642 μg kg-1. Graphical Abstract Analysis of polar compounds in soy-based nutraceutical products.


Enhanced Figures of Merit for a High-Performing Actuator in Electrostrictive Materials.
The overall performance of an electrostrictive polymer is rated by characteristic numbers, such as its transverse strain, blocking force, and energy density, which are clearly limited by several parameters. Besides the geometrical impact, intrinsic material parameters, such as the permittivity coefficient as well as the Young's modulus and the breakdown electric field, have strong influences on the actuation properties of an electroactive polymer and thus on the device's overall behavior. As a result, an analysis of the figures of merit (FOMs) involving all relevant material parameters for the transverse strain, the blocking force, and the energy density was carried out, making it possible to determine the choice of polymer matrix in order to achieve a high actuator performance. Another purpose of this work was to demonstrate the possibility of accurately measuring the free deflection without the application of an external force and inversely measuring the blocking force under quasi-static displacement. The experimental results show good electrostrictive characteristics of the plasticized terpolymer under relatively low electric fields.


Long-Term Evolution of Burkholderia multivorans during a Chronic Cystic Fibrosis Infection Reveals Shifting Forces of Selection.
Burkholderia multivorans is an opportunistic pathogen capable of causing severe disease in patients with cystic fibrosis (CF). Patients may be chronically infected for years, during which the bacterial population evolves in response to unknown forces. Here we analyze the genomic and functional evolution of a B. multivorans infection that was sequentially sampled from a CF patient over 20 years. The population diversified into at least four primary, coexisting clades with distinct evolutionary dynamics. The average substitution rate was only 2.4 mutations/year, but notably, some lineages evolved more slowly, whereas one diversified more rapidly by mostly nonsynonymous mutations. Ten loci, mostly involved in gene expression regulation and lipid metabolism, acquired three or more independent mutations and define likely targets of selection. Further, a broad range of phenotypes changed in association with the evolved mutations; they included antimicrobial resistance, biofilm regulation, and the presentation of lipopolysaccharide O-antigen repeats, which was directly caused by evolved mutations. Additionally, early isolates acquired mutations in genes involved in cyclic di-GMP (c-di-GMP) metabolism that associated with increased c-di-GMP intracellular levels. Accordingly, these isolates showed lower motility and increased biofilm formation and adhesion to CFBE41o- epithelial cells than the initial isolate, and each of these phenotypes is an important trait for bacterial persistence. The timing of the emergence of this clade of more adherent genotypes correlated with the period of greatest decline in the patient's lung function. All together, our observations suggest that selection on B. multivorans populations during long-term colonization of CF patient lungs either directly or indirectly targets adherence, metabolism, and changes in the cell envelope related to adaptation to the biofilm lifestyle. IMPORTANCE Bacteria may become genetically and phenotypically diverse during long-term colonization of cystic fibrosis (CF) patient lungs, yet our understanding of within-host evolutionary processes during these infections is lacking. Here we combined current genome sequencing technologies and detailed phenotypic profiling of the opportunistic pathogen Burkholderia multivorans using sequential isolates sampled from a CF patient over 20 years. The evolutionary history of these isolates highlighted bacterial genes and pathways that were likely subject to strong selection within the host and were associated with altered phenotypes, such as biofilm production, motility, and antimicrobial resistance. Importantly, multiple lineages coexisted for years or even decades within the infection, and the period of diversification within the dominant lineage was associated with deterioration of the patient's lung function. Identifying traits under strong selection during chronic infection not only sheds new light onto Burkholderia evolution but also sets the stage for tailored therapeutics targeting the prevailing lineages associated with disease progression.


SnakeCube: containerized and automated pipeline for de novo genome assembly in HPC environments.
The rapid progress in sequencing technology and related bioinformatics tools aims at disentangling diversity and conservation issues through genome analyses. The foremost challenges of the field involve coping with questions emerging from the swift development and application of new algorithms, as well as the establishment of standardized analysis approaches that promote transparency and transferability in research. Here, we present SnakeCube, an automated and containerized whole de novo genome assembly pipeline that runs within isolated, secured environments and scales for use in High Performance Computing (HPC) domains. SnakeCube was optimized for its performance and tested for its effectiveness with various inputs, highlighting its safe and robust universal use in the field.


Empirical constrained Bayes predictors accounting for non-detects among repeated measures.
When the prediction of subject-specific random effects is of interest, constrained Bayes predictors (CB) have been shown to reduce the shrinkage of the widely accepted Bayes predictor while still maintaining desirable properties, such as optimizing mean-square error subsequent to matching the first two moments of the random effects of interest. However, occupational exposure and other epidemiologic (e.g. HIV) studies often present a further challenge because data may fall below the measuring instrument's limit of detection. Although methodology exists in the literature to compute Bayes estimates in the presence of non-detects (Bayes(ND)), CB methodology has not been proposed in this setting. By combining methodologies for computing CBs and Bayes(ND), we introduce two novel CBs that accommodate an arbitrary number of observable and non-detectable measurements per subject. Based on application to real data sets (e.g. occupational exposure, HIV RNA) and simulation studies, these CB predictors are markedly superior to the Bayes predictor and to alternative predictors computed using ad hoc methods in terms of meeting the goal of matching the first two moments of the true random effects distribution.


Deciphering acoustic emission signals in drought stressed branches: the missing link between source and sensor.
When drought occurs in plants, acoustic emission (AE) signals can be detected, but the actual causes of these signals are still unknown. By analyzing the waveforms of the measured signals, it should, however, be possible to trace the characteristics of the AE source and get information about the underlying physiological processes. A problem encountered during this analysis is that the waveform changes significantly from source to sensor and lack of knowledge on wave propagation impedes research progress made in this field. We used finite element modeling and the well-known pencil lead break source to investigate wave propagation in a branch. A cylindrical rod of polyvinyl chloride was first used to identify the theoretical propagation modes. Two wave propagation modes could be distinguished and we used the finite element model to interpret their behavior in terms of source position for both the PVC rod and a wooden rod. Both wave propagation modes were also identified in drying-induced signals from woody branches, and we used the obtained insights to provide recommendations for further AE research in plant science.


Effects of treatment of sleep disorders on sleep, psychological and cognitive functioning and biomarkers in individuals with HIV/AIDS and under methadone maintenance therapy.
Poor sleep is a major complaint of people with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) and undergoing methadone maintenance therapy (MMT). We tested the impact of three different sleep-improving interventions (trazodone; sleep hygiene training; sleep hygiene training + trazodone) on sleep, psychological functioning and biomarkers in males with HIV and undergoing MMT. A total of 75 male outpatients (mean age: 39.6 years) participated in a 12 week intervention. Participants were randomly assigned to one of the following conditions: trazodone 50 mg/d (TRAZ); sleep hygiene training (SHT); sleep hygiene training and trazodone (SHT + TRAZ). At baseline, and six and 12 weeks later, participants completed questionnaires covering subjective sleep and daytime sleepiness, and symptoms of depression and anxiety. In parallel, their cognitive performance (working memory; sustained attention) was assessed. Biomarkers (cortisol, BNDF, CD4+) were assessed at baseline and at the end of the study. Over time, sleep disturbances decreased and daytime functioning and overall sleep quality improved. More specifically, both sleep disturbances and daytime functioning improved in the two SHT conditions from baseline to week 6. Daytime functioning remained stable from week 6 to week 12. Over time, in all conditions symptoms of depression and anxiety declined from baseline to week 6 and remained lower from week 6 to week 12. Daytime sleepiness, symptoms of insomnia and sleep-disordered breathing remained unchanged. Sustained attention performance improved over time from baseline to week 6 and remained high through to week 12. Biomarkers remained unchanged. In males with HIV and undergoing MMT, treating sleep disturbances over a period of six to 12 weeks had a positive impact on aspects of sleep disturbance, symptoms of depression and anxiety, and cognitive performance. The results indicate that sleep hygiene training, either as stand-alone or in combination with trazodone, can produce positive results.


Serotonin in affective control.
Serotonin is a neuromodulator that is extensively entangled in fundamental aspects of brain function and behavior. We present a computational view of its involvement in the control of appetitively and aversively motivated actions. We first describe a range of its effects in invertebrates, endowing specific structurally fixed networks with plasticity at multiple spatial and temporal scales. We then consider its rather widespread distribution in the mammalian brain. We argue that this is associated with a more unified representational and functional role in aversive processing that is amenable to computational analyses with the kinds of reinforcement learning techniques that have helped elucidate dopamine's role in appetitive behavior. Finally, we suggest that it is only a partial reflection of dopamine because of essential asymmetries between the natural statistics of rewards and punishments.


Efficacy of two methods for restorative materials' removal in primary teeth.
This in vitro study aimed to compare the time required for removal, the presence of residues of restorative material, tooth structure loss and dental surface morphology after removal of composite resin and amalgam restorations from occlusal cavities in primary molars using conventional high-speed bur and CVDentus® ultrasonic diamond tips. A total of 37 primary molars were allocated into four groups: Group 1 (n=9)-amalgam restorations removed using high-speed bur; Group 2 (n=10)-amalgam restorations removed using ultrasonic tip; Group 3 (n=8)- composite resin restorations removed using high-speed bur; Group 4 (n=10)-composite resin restorations removed using ultrasonic tip. After being restored, teeth were sectioned and analyzed through stereoscopic microscope images before and after restoration removal. The structural loss was analyzed by software of image analysis, and an examiner assessed for the presence of residues. Scanning electron microscopy was used to evaluate the morphology. Time and structural loss values were compared using ANOVA, and the percentages of samples with residues using Fisher test. There was no statistically significant difference in the tooth structure loss among different methods and restorative materials, as well as in the presence of residues of restorative material. However, diamond burs were faster than the ultrasonic method for both materials. Differences in dental morphology were observed between the methods of restoration removal, but not related to the restorative material. Both conventional high-speed bur and ultrasonic diamond tip methods remove similar amounts of tooth structure, but the removal performed with diamond tips in ultrasonic devices is slower. This study shows that both ultrasonic and conventional high-speed bur methods for removing restorations generate similar loss of sound dental tissue, but the former is slower.


Age-Related Medicine.
A meeting organised by the Academy of Pharmaceutical Sciences focussed on the challenges of developing medicines for older adults. International experts discussed the complexity introduced by polypharmacy and multiple morbidities and how the risk⁻benefit ratio of a medicine changes as an individual ages. The way in which regulatory authorities are encouraging the development of age-appropriate medicines was highlighted. Examples were provided of the difficulties faced by the older population with some medicinal products and suggestions given as to how the pharmaceutical scientist can build the requirements of the older population into their development of new medicines, as well as improvements to existing ones.


Synovial sarcoma of the larynx treated by supraglottic laryngectomy: case report and literature review.
We describe a case of synovial sarcoma of the larynx, and we discuss the use of fluorescence in situ hybridization (FISH) in confirming the diagnosis. The patient was a 21-year-old woman who presented with a recurrence of a previously resected supraglottic tumor of the aryepiglottic folds. A horizontal supraglottic laryngectomy was performed, and the 0.5-cm tumor was resected. Histopathologic study suggested that it was a biphasic malignant tumor compatible with a synovial sarcoma. The diagnosis of synovial sarcoma was confirmed by FISH immunohistochemistry with the use of an SYT break-apart probe. The patient recovered satisfactorily, but at follow-up 5 years and 4 months later, tumoral activity was evident in the left side of the neck. A biopsy found that 5 lymph nodes contained a metastasis of the synovial sarcoma. Again, a bilateral neck dissection was performed, and it revealed that 16 of 16 right-side nodes and 36 of 36 left-side nodes were negative. Two months later, the patient received 46 Gy of radiotherapy in 23 sessions. She remained free of disease during 2 more years of follow-up. Synovial sarcoma of the larynx is a rare entity. Organ preservation seems to be indicated in these cases. The histologic diagnosis may be difficult. In this case, the identification of a genetic mutation corroborated the diagnosis.


[Studies on prediction of visual function of vitreous opacity patients by Vernier hyperacuity tests].
To evaluate the clinical value of visual function with vitreous opacity patients preoperatively. The vernier acuity examining soft wear system was developed to detect the 14 cases (14 eyes) with vitreous opacity patients preoperatively. Two fixed targets and a movable target are shown on the computer screen. The examine was asked to adjust the position of the central target and the relationship between it and align them by using a track-ball. The computer automatically recorded the deviations of distances between the movable target and the specific one, and computed the average threshold of hyperacuity and its variance. Then the hyperacuity result and postoperative visual acuity were compared. Paired t-test showed that the difference between peroperative and postoperative vernier acuity thresholds was not significant (t = 0. 52, P = 0. 612). The coefficient of correlation was 0. 85 (P < 0. 01). Neither was the threshold variance (t = 0. 431, P = 0. 674). The correlation coefficient was 0.97 (P < 0.01). The correlation coefficient between preoperative hyperacuity threshold and postoperative visual acuity was -0.74 (P < 0.01), and that between preoperative threshold variance and postoperative visual acuity was -0.95 (P < 0.01). Based on the preoperative vernier acuity threshold and its variance, the function of linear regression was Y = 0.943 - 0.000116THv - 0.00193SDv. Vernier acuity remains good consistency after vitrectomy, and it is one of the sensitive parameter in predicting the postoperative visual function for vitreous opacities.


Novel pathway to the growth of diamond on cubic beta-SiC(001).
By carrying out first-principles calculations on diamond-forming processes, we predict a method for the heteroepitaxial growth of diamond on cubic beta-SiC(001). In the method, we used two processes: (i) the preformation of an sp(3)-like surface configuration of beta-SiC(001) by the adsorption of group-V surfactants; (ii) the successive growth of diamond by the segregation of the surfactants onto a surface and the desorption of surface hydrogen. Analyzing the segregation energies, we found that the atomic size effect plays a crucial role in the surfactant-mediated growth of diamond on beta-SiC(001).


Recovery of lymphocyte and dendritic cell subsets following reduced intensity allogeneic bone marrow transplantation.
Approaches using reduced conditioning regimens have been developed to obtain minimal procedure-related toxicity. Such novel therapeutic options are being explored with good preliminary results concerning feasibility and engraftment. However, many aspects remain under-evaluated and few data are available about immune and dendritic cell (DC) reconstitution after these highly immunosuppressive regimens. We present here our data in 20 patients receiving allogeneic bone marrow transplantation (allo-BMT) using a reduced preparative regimen. We evaluated in the first 3 months following allo-BMT, several immunological parameters including DC subsets, and compared these to historical results obtained in a group of myeloablative allo-BMT patients. We found an early recovery of leukocytes, CD8+ and NK lymphocytes. We also found a trend towards an improved B cell recovery. These results are somewhat in contrast to the altered immune recovery observed in the myeloablative setting. In addition, we found a significant early circulating DC recovery. Circulating blood DCs were also found to be of full donor origin as assessed by FISH in sex-mismatched pairs. Nevertheless, naive CD4 + CD45RA + T cells were found to be profoundly reduced following such regimens.Collectively, these data further enhance the overall benefits of reduced intensity regimens and the need for a stringent biological monitoring for assessment of the potential advantages of reduced intensity allo-BMT in comparison with conventional allo-BMT.


Molecular mechanism for orienting membrane and actin dynamics to nascent cell-cell contacts in epithelial cells.
The small GTPase Rac1 has been implicated in regulation of cell migration and cell-cell adhesion in epithelial cells. Little is known, however, about the spatial and temporal coordination of Rac1 activity required to balance these competing processes. We fractionated endogenous Rac1-containing protein complexes from membranes of Madin-Darby canine kidney cells and identified three major complexes comprising a Rac1.PAK (p21-activated kinase) complex, and 11 S and 16 S Rac1 complexes. Significantly, Rac1 shifts from the 11 S to a 16 S particle during initiation of cell-cell adhesion. This shift may reflect a diffusion trapping mechanism by which these Rac1 complexes are localized to cadherin-mediated cell-cell contacts through an interaction with annexin II.


Ultrastructure of the olfactory epithelium in a flatfish, barfin flounder (Verasper moseri).
In this study, we examined the olfactory epithelium (OE) of the barfin flounder by transmission electron microscopy. As in the case of the ordinary teleost, the OE of the barfin flounder had 3 types of olfactory receptor cells (ciliated olfactory receptor cell, microvillous olfactory receptor cell and crypt cell), 3 types of supporting cells (ciliated, microvillous and crypt supporting cells) and basal cells. Each type of OE cells in the barfin flounder had similar ultrastructure to that of the ordinary teleost. Crypt cell is the third type of olfactory receptor cell unique to fish, whose function is unclear. The barfin flounder may be a suitable material to study crypt cells because it has relatively abundant crypt cells in the OE.


[Preparation and photocatalytic activity of boron doped CeO2/TiO2 mixed oxides].
Boron doped CeO2/TiO2 mixed oxides photocatalysts were prepared by adding boric acid and cerous nitrate during the hydrolyzation of titanium trichloride and tetrabutyl titanate. XRD, UV-Vis DRS and XPS techniques were used to characterize the crystalline structure, light absorbing ability and the chemical state of Boron element in the photocatalyst sample. The photocatalytic activities were evaluated by monitoring the degradation of acid red B under UV irradiation. These results indicate that the wavelengths at adsorbing edge are affected by the content of cerous nitrate and the maximum absorption wavelength is about 481 nm when the mole ratio of Ce/Ti is 1.0. For higher dosage of Cerium, the absorbance edge shifts to blue slightly. The prepared photocatalyst is composed of anatase TiO2 and cubic CeO2 when calcined at 500 degrees C. An increase in the calcination temperature transforms the crystalline structure of the titanium oxides from anatase to rutile, and has no obvious influence on crystalline structure of CeO2 but crystallites growth up. The absorbance edge decreases drastically with the increase of calcination temperature. With a view to the stability of photocatalyst and utilization of sun energy, 500 degrees C of calcination temperature is recommended. The XP spectrum for B1s exhibits that only a few boron ions dope into titania and ceria matrix, others exist in B2O3. The photocatalytic activity increases with increase of cerous nitrate dosage, and decreases drastically due to higher dosage (the mol ratio of Ce/Ti > 0.5). After 10 min UV irradiation, 96% of acid red B is degraded completely over photocatalyst under optimum reaction condition.


Associations among family adaptability and cohesion, interparental conflict, and tactics used during young adults' conflict with parents.
The current study examined the association among characteristics of the marital relationship, family environment, and young adults' conflict interactions with parents. Reports from 124 17- to 20-yr.-olds indicated tactics used during conflicts with parents were associated with perceived magnitude of interparental conflict and family cohesion. Further, reports of frequency of conflict with parents were associated with young adults' use of aggressive conflict tactics. The current study indicates how young adults' perceptions of family adaptability and cohesion moderated the association between perceptions of interparental conflict and their reports of using aggressive tactics during conflict with parents. Findings are discussed in terms of implications of the associations among the marital relationship, family environment, and young adults' relationships with parents.


Development of a continuum damage model to predict accumulation of sub-failure damage in tendons.
Many painful and physically debilitating conditions involve sub-failure mechanical damage to seemingly intact connective tissues such as tendons and ligaments. We found that the amount of denatured collagen in rat tail tendon (RTT) fascicles increased over experiments of cyclic loading to a constant load level (creep cyclic fatigue) with fluorescently tagged collagen hybridizing peptides (CHPs) that bind to denatured collagen. To better understand tendon sub-failure damage progression, computational modeling of tendon materials via finite element analysis in FEBio has been conducted. The objective of this project was to develop, implement, and test the ability of a new continuum damage mechanics (CDM) model in FEBio to represent the sub-failure damage behavior seen in our RTT fascicle creep cyclic fatigue experimental data. There appeared to be two distinct mechanisms responsible for the creep cyclic fatigue softening behavior of RTT fascicles over the number of cycles to failure: the preconditioning effect and overall collagen damage. In our finite element (FE) models, the RTT fascicle undamaged elastic constitutive material was composed of a matrix and fibers described by the Coupled Veronda-Westmann and exponential-linear materials. This undamaged elastic material was convolved with a modified CDM model adapted from Balzani et al., in 2012. The novelty of the Balzani damage model is the inclusion of two interrelated mechanisms described as continuous and discontinuous damage. The continuous damage formulation calculates damage accumulation during the loading and reloading of each new cycle, while the discontinuous damage approach accumulates damage from the maximum strain over the loading history to the current time. We modified the Balzani damage model formulations to represent exponential and sigmoidal increases in damage marked by the preconditioning effect and collagen damage in RTT fascicles as functions of continuous and discontinuous damage. The original Balzani damage model was first verified, then the modified CDM model was implemented into FEBio and used to reproduce the sample specific experimental creep cyclic fatigue stress-strain data as well as predict incremental cyclic fatigue. The resulting model will be useful for future experimental and computational studies of damage mechanics to understand tendon pathologies.


Structure and reaction mechanism of L-rhamnulose kinase from Escherichia coli.
Bacterial L-rhamnulose kinase participates in the degradation of L-rhamnose, which is ubiquitous and particularly abundant in some plants. The enzyme catalyzes the transfer of the gamma-phosphate group from ATP to the 1-hydroxyl group of L-rhamnulose. We determined the crystal structures of the substrate-free kinase and of a complex between the enzyme, ADP and L-fructose, which besides rhamnulose is also processed. According to its chainfold, the kinase belongs to the hexokinase-hsp70-actin superfamily. The closest structurally known homologue is glycerol kinase. The reported structures reveal a large conformational change on substrate binding as well as the key residues involved in catalysis. The substrates ADP and beta-L-fructose are in an ideal position to define a direct in-line phosphoryl transfer through a bipyramidal pentavalent intermediate. The enzyme contains one disulfide bridge at a position where two homologous glycerol kinases are regulated by phosphorylation and effector binding, respectively, and it has two more pairs of cysteine residues near the surface that are poised for bridging. However, identical catalytic rates were observed for the enzyme in reducing and oxidizing environments, suggesting that regulation by disulfide formation is unlikely.


Structure and functions of the 20S and 26S proteasomes.
The proteasome is an essential component of the ATP-dependent proteolytic pathway in eukaryotic cells and is responsible for the degradation of most cellular proteins. The 20S (700-kDa) proteasome contains multiple peptidase activities that function through a new type of proteolytic mechanism involving a threonine active site. The 26S (2000-kDa) complex, which degrades ubiquitinated proteins, contains in addition to the 20S proteasome a 19S regulatory complex composed of multiple ATPases and components necessary for binding protein substrates. The proteasome has been highly conserved during eukaryotic evolution, and simpler forms are even found in archaebacteria and eubacteria. Major advances have been achieved recently in our knowledge about the molecular organization of the 20S and 19S particles, their subunits, the proteasome's role in MHC-class 1 antigen presentation, and regulators of its activities. This article focuses on recent progress concerning the biochemical mechanisms and intracellular functions of the 20S and 26S proteasomes.


Ibuprofen and Alzheimer's disease.
There is epidemiological observation that long-term treatment of patients suffering from rheumatoid arthritis with ibuprofen results in reduced risk and delayed onset of Alzheimer's disease (AD). Chronic central nervous system inflammation in AD brain is implicated in the pathology, but how ibuprofen impacts the pathogenic AD pathways is unclear. Ibuprofen, a commonly used over-the-counter nonsteroidal anti-inflammatory drug (NSAID) that is a cyclooxygenase (COX)-1 and COX-2 inhibitor as well as a peroxisome proliferator-activated receptor (PPAR) agonist, decreases the production of nitric oxide (NO), protects neurons against glutamate toxicity and decreases the production of proinflammatory cytokines. Ibuprofen crosses the blood brain barrier and suppresses neuritic plaque pathology and inflammation in AD brain. Furthermore, ibuprofen is a potent free radical scavenger, and it could reduce lipid peroxidation and free radical generation. Because of neuroprotective activity, relative safety, and its long history of use, ibuprofen is currently being developed for clinical use in AD. Ibuprofen may be a promising new therapeutic avenue for the treatment of neurodegenerative diseases such as AD.


Localization of the site of origin of cardiac activation by means of a heart-model-based electrocardiographic imaging approach.
We have developed a new approach to solve the inverse problem of electrocardiography in terms of heart model parameters. The inverse solution of the electrocardiogram (ECG) inverse problem is defined, in the present study, as the parameters of the heart model, which are closely related to the physiological and pathophysiological status of the heart, and is estimated by using an optimization system of heart model parameters, instead of solving the matrix equation relating the body surface ECGs and equivalent cardiac sources. An artificial neural network based preliminary diagnosis system has been developed to limit the searching space of the optimization algorithm and to initialize the model parameters in the computer heart model. The optimal heart model parameters were obtained by minimizing the objective functions, as functions of the observed and model-generated body surface ECGs. We have tested the feasibility of the newly developed technique in localizing the site of origin of cardiac activation using a pace mapping protocol. The present computer simulation results show that, the present approach for localization of the site of origin of ventricular activation achieved an averaged localization error of about 3 mm [for 5-muV Gaussian white noise (GWN)] and 4 mm (for 10-muV GWN), with standard deviation of the localization errors of being about 1.5 mm. The present simulation study suggests that this newly developed approach provides a robust inverse solution, circumventing the difficulties of the ECG inverse problem, and may become an important alternative to other ECG inverse solutions.


Spatial and Temporal Distribution of Rodents during the Epizootic and Enzootic Periods of Plague, with a Focus on Exu, Northeastern Brazil.
The plague caused by the Yersinia pestis bacterium is primarily a flea-transmitted zoonosis of rodents that can also be conveyed to humans and other mammals. In this work, we analyzed the spatial and temporal distribution of rodent populations during epizootic and enzootic periods of the plague in the municipality of Exu, northeastern Brazil. The geospatial analyses showed that all the rodent species appeared through the whole territory of the municipality, with different occurrence hotspots for the different species. Important fluctuations in the rodent populations were observed, with a reduction in the wild rodent fauna following the end of a plague epizootic period, mostly represented by Necromys lasiurus and an increase in the commensal species Rattus rattus. A higher abundance of rats might lead to an increased exposure of human populations, favoring spillovers of plague and other rodent-borne diseases. Our analysis highlights the role of wild rodent species as amplifier hosts and of commensal rats (R. rattus) as preserver hosts in the enzootic period of a specific transmission infection area.


[Hereditary prostate cancer].
About 10% of the prostate cancer cases were recognized as familial or hereditary. Till now gene/genes responsible for hereditary prostate cancer are not identified. Hereditary prostate cancer case concerning 3 brothers in family of 6 siblings from first marriage and a grandson from second marriage was presented. Two brothers were treated radical prostatectomy because of confined disease. The third brother with spreading disease died after androgen blockade management. We did not find any linkage between chosen markers of PCaP region (Predisposing for Prostate Cancer) and prostate cancer occurrence in this family.


Adult ECG criteria for left ventricular hypertrophy in young competitive athletes.
Time-tested data indicate that ECG diagnosis of left ventricular hypertrophy in young athletes is challenging due to low sensitivity of the commonly used criteria. We sought to establish whether adult ECG criteria can be appropriate to make diagnosis of both common and uncommon patterns of left ventricular hypertrophy in young trained athletes. A total of 122 athletes, ages 16.2±3.8 years, training at least 5 h per week, were studied with Sokolow-Lyon voltage, Romhilt-Estes, Cornell voltage, Cornell Product, Perugia and Framingham scores. Garson Criteria were also investigated in athletes under 16. Participants were divided into 2 groups based on the presence (group-A, n=56) or absence (group-B, n=66) of at least one positive ECG score. Test performance was calculated with respect to accurate echocardiographic diagnosis of left ventricular hypertrophy. There were no inter-group differences regarding physical characteristics and training burden. 9 athletes from group-A (16%) and 2 from group-B (3%) were found to have left ventricular hypertrophy, likely to be pathological in 2 cases from group-A. Criteria gathering both QRS voltages and ST-T anomalies, like Perugia-score, best identified this subgroup and should be preferred to those based on QRS voltage analysis alone.


The Effect of the Premedication with Systemic Corticosteroids and Antibiotics on Inflammation and Intraoperative Bleeding During Sinonasal Endoscopic Surgery for Chronic Rhinosinusitis with Nasal Polyps (CRSwNP).
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a disease characterized by a variety of inflammatory mechanisms. Extensive genetic analyses have shown that among the molecules that are involved in its genetic base, interleukins (ILs) play a critical role in the development and progression of CRSwNP. ILs, such us IL-4 (5q31.1), IL-5 (5q31.1), IL-13 (5q31.11), and IL-25 (14q11.2) are found to be overexpressed. Our aim is to investigate, through a systemic review, the effect of the premedication with systemic corticosteroids and antibiotics on inflammation and intraoperative bleeding during sinonasal endoscopic surgery for CRSwNP. The search period covered January 1979 to February 2021, using the scientific databases PubMed, Scien-ceDirect, Scopus, Cochrane Library και Google Scholar. Search terms were "effect, premedication, systemic corticosteroids, antibiotics, intraoperative, bleeding, inflammation, sinonasal, endoscopic surgery, chronic rhinosinusitis, and nasal polyposis." From an initial 80 titles found in the above medline databases, the evaluations led to the final inclusion of 15 papers. Eighty titles found in the above medline databases. Eleven titles were excluded as they did not include a summary and full text in English language. Sixty-nine titles collected and duplicate references were searched. Twelve titles were excluded due to double reporting. Fifty-seven articles remained for systematic review. Fourty-two articles were excluded after systematic review and correlation with the research field. Fifteen articles were eventually included in the literature review. The effect of corticosteroids and antibiotics on the size of nasal polyps, nasal symptoms, and systemic markers of inflammation is significant. Each of the above factors acts on different pathogenetic inflammatory mechanisms.The use of perioperative corticosteroids reduces blood loss and operation time and improves the quality of the surgical field. There are no other medications that have been shown to improve the surgical field and outcome. Whether there is an additive effect on systemic corticosteroids on top of nasal corticosteroids is unclear. The european position paper on rhinosinusitis and nasal polyps steering group advises to use (nasal) corticosteroids before endoscopic sinus surgery.However, it should be considered in future studies whether some minor differences are due to differences in the initial doses of corticosteroids or during treatment in the preoperative period. It is worth mentioning that although high doses of corticosteroids are required to control the progression of rhinosinusitis with nasal polyps, the optimal initial dosage and the total duration of the treatment have not yet been standardized in patients with CRSwNP and future studies are required to determine the 2 above parameters (optimal dosage and duration of treatment). There are, therefore, known risks from corticosteroid administration, and clinicians should consider them when evaluating each patient. Each patient should be considered as an individual case with individualized treatment.


Relationship between postprandial esophageal acid exposure and meal volume and fat content.
The effect of meal volume and fat content on gastroesophageal reflux was investigated in 20 asymptomatic healthy subjects. In each subject, intraesophageal pH monitoring was performed during a 3-hr postprandial period (PP) in the same position (supine or upright) on two successive days. On day 1, 500-ml low- and high-fat meals were ingested and, on day 2, an 800-ml low-fat meal was ingested. The acid exposure time was assessed as the percentage of time with a pH < 4.0. The acid exposure time in subjects in the upright position was significantly longer in the 800-ml group than in the 500-ml group for the entire PP (2.7 +/- 1.5%; mean +/- SE, 0.7 +/- 0.4%; P < 0.05). Of subjects in the supine position, the high-fat group showed significantly longer acid exposure time than the low-fat group both for the entire PP (7.6 +/- 3.0%, 0.7 +/- 0.5%; p < 0.05) and for the second hour (P < 0.05). We have demonstrated that differences in the meal volume and fat content influence gastroesophageal reflux in healthy asymptomatic subjects and that this influence varies with the position.


Possible adverse effect of chromium in occupational exposure of tannery workers.
Our aim was to investigate the adverse effects of occupational exposure to trivalent chromium. We measured chromium and iron levels in serum and urine and hemoglobin levels in tannery workers and unexposed persons. We studied three groups of subjects. Group 1 included 15 non-smoking male tannery workers highly exposed to chromium from tanning and retanning departments. Group 2 included 14 non-smoking male tannery workers with moderate chromium exposure from dying, drying and finishing departments. Group 3 included 11 healthy, non-smoking male subjects without direct chromium exposure. Higher serum chromium levels were observed in groups 1 and 2 with respect to group 3 (mean values respectively: 0.43; 0.25 and 0.13 microg x l(-1)). Urine chromium levels in group 1 were higher than those in controls (mean values: 1.78 and 1.35 microg x l(-1)). In group 1 an inverse association was found between serum chromium and urine iron (-0.524), urine chromium and hemoglobin (-0.594) and between the urine chromium to iron ratio and hemoglobin (-0.693, p<0.05). The results suggest a chromium adverse effect on iron metabolism, possibly associated with excessive body chromium accumulation. In conclusion, chromium urine test could be recommended for diagnosis of chromium adverse effect on iron metabolism. Further studies are needed to quantify the relationship between urine chromium and hemoglobin metabolism.


[Diagnosis of non-organic dysphonia in adult].
Non organic dysphonia or functional voice disorders are the consequence of a vocal misuse or overuse with inefficient oral communication. Any stage of voice production can be altered. A review of physiopathological, aerodynamic and biomechanical mechanisms will help to understand the onset of dysphonia. Organic lesions as a consequence of functional voice disorders are frequent but the link is not easy to establish. It is important to look for various physiologic, anatomic, environmental, behavioural and infectious factors that could induce or aggravate non organic dysphonia, as they can benefit from specific treatment. A thorough functional and organic assessment is the first step of the rehabilitation process, taking into account the patient's expectations about his voice handicap.


Autopsy study of infant kidneys in cases of urinary tract anomalies.
The infant autopsies were scrutinised to find the incidence, etiology & significance in terms of fatality of urinary tract anomalies. On analysing 1329 infant autopsies, 24 cases (1.8%) of significant urinary tract anomalies were found. There was marked male predominance. Intrauterine obstruction of urinary tract was the main etiological factor leading to dysplastic changes in the renal tissue. Dysplasia is severe in extent and may be associated with persistent blastemal zones when the obstruction is complete & bilateral in nature.


Introduction and expression of the bacterial PaeR7 restriction endonuclease gene in mouse cells containing the PaeR7 methylase.
To study the factors essential for a functional restriction system, the PaeR7 restriction-modification system has been introduced and expressed in murine cells. Transfer of this system was accomplished in two steps. First, cells containing sufficient PaeR7 methylase to completely methylate the mouse genome were constructed. In the second step, the mouse metallothionein promoter-regulated, endonuclease expression vector linked to the hygromycin B resistance selection marker was used to transfect the high methylase-expressing cells. Sixty percent of the clones isolated contained PaeR7 endonuclease enzymatic activity. Transfected cells expressing both methylase and endonuclease were incapable of blocking infection by DNA viruses, and possible explanations are discussed.


Pentatomic cyclic agonists and muscarinic receptors: a 20 years review.
The results of 20 years of structure-activity relationship (SAR) studies of pentatomic cyclic agonists on muscarinic receptors are reported and commented. Our results are compared with the findings obtained from quantitative structure-activity relationship (QSAR) studies and from those of molecular biology. The results from all three approaches point in the same direction and should help in the future design of new muscarinic agonists.


Multidisciplinary patient education for total joint replacement surgery patients.
The purpose of this article is to describe a preadmission, preoperative educational program offered free of charge for patients undergoing total joint replacement surgery at a large teaching hospital located in metropolitan Detroit, Michigan. In establishing the preoperative educational program, a multidisciplinary approach was used to provide a comprehensive learning environment for patients and their families. To evaluate the effectiveness of the program, patients completed surveys at the end of each class. Patients reported that their expectations of the program were met, they were less anxious about their surgery as a result of attending the classes, and the preoperative teaching by the multidisciplinary team was effective. Having a live session that offered an opportunity to ask individual and specific questions to each healthcare professional with immediate feedback proved to be a positive experience for patients. Patients' comments supported the multidisciplinary team's impression that real-time, interactive teaching was highly valued by patients and their caregivers.


The role of AKT/mTOR pathway in stress response to UV-irradiation: implication in skin carcinogenesis by regulation of apoptosis, autophagy and senescence.
Induction of DNA damage by UVB and UVA radiation may generate mutations and genomic instability leading to carcinogenesis. Therefore, skin cells being repeatedly exposed to ultraviolet (UV) light have acquired multilayered protective mechanisms to avoid malignant transformation. Besides extensive DNA repair mechanisms, the damaged skin cells can be eliminated by induction of apoptosis, which is mediated through the action of tumor suppressor p53. In order to prevent the excessive loss of skin cells and to maintain the skin barrier function, apoptotic pathways are counteracted by anti-apoptotic signaling including the AKT/mTOR pathway. However, AKT/mTOR not only prevents cell death, but is also active in cell cycle transition and hyper-proliferation, thereby also counteracting p53. In turn, AKT/mTOR is tuned down by the negative regulators being controlled by the p53. This inhibition of AKT/mTOR, in combination with transactivation of damage-regulated autophagy modulators, guides the p53-mediated elimination of damaged cellular components by autophagic clearance. Alternatively, p53 irreversibly blocks cell cycle progression to prevent AKT/mTOR-driven proliferation, thereby inducing premature senescence. Conclusively, AKT/mTOR via an extensive cross talk with p53 influences the UV response in the skin with no black and white scenario deciding over death or survival.


Economic Impact of the 2015 MERS Outbreak on the Republic of Korea's Tourism-Related Industries.
The 2015 Middle East respiratory syndrome (MERS) outbreak in the Republic of Korea (ROK) is an example of an infectious disease outbreak initiated by international travelers to a high-income country. This study was conducted to determine the economic impact of the MERS outbreak on the tourism and travel-related service sectors, including accommodation, food and beverage, and transportation, in the ROK. We projected monthly numbers of noncitizen arrivals and indices of services for 3 travel-related service sectors during and after the MERS outbreak (June 2015 to June 2016) using seasonal autoregressive integrated moving average models. Tourism losses were estimated by multiplying the monthly differences between projected and actual numbers of noncitizen arrivals by average tourism expenditure per capita. Estimated tourism losses were allocated to travel-related service sectors to understand the distribution of losses across service sectors. The MERS outbreak was correlated with a reduction of 2.1 million noncitizen visitors corresponding with US$2.6 billion in tourism loss for the ROK. Estimated losses in the accommodation, food and beverage service, and transportation sectors associated with the decrease of noncitizen visitors were US$542 million, US$359 million, and US$106 million, respectively. The losses were demonstrated by lower than expected indices of services for the accommodation and food and beverage service sectors in June and July 2015 and for the transportation sector in June 2015. The results support previous findings that public health emergencies due to traveler-associated outbreaks of infectious diseases can cause significant losses to the broader economies of affected countries.


Arylamine drugs: genotoxic-carcinogenic activity of NO-derivatives.
This review provides information on arylamine drugs which have been tested for the formation of N-nitroso compounds (NOC) by reacting with nitrite, and on the genotoxic-carcinogenic effects of their nitrosation products. In an extensive search we have found that 109 arylamine drugs were examined for their ability to react with nitrite, and 105 of them (96.3 %) were found to form NOC or in some cases other reactive species. Moreover, 78 arylamine drugs were examined in short-term genotoxicity tests and/or in long-term carcinogenicity assays, either in combination with nitrite or using their nitrosation product; 67 of them (85.9 %) have been found to give at least one positive response. Only a small fraction, the 19.1 % of theoretically nitrosatable arylamine drugs, has been examined for the possible formation of genotoxic-carcinogenic NOC, guidelines for genotoxicity testing of pharmaceuticals do not indicate the need of appropriate tests, and patients are not informed that the drug-nitrite interaction and the consequent risk can be reduced to a large extent by consuming the nitrosatable drug with ascorbic acid.


Lipoprotein (a) concentrations in patients with various dyslipidaemias.
Although the genetic background is the most important determinant of lipoprotein (a) (Lp(a)) concentration other factors, such as coexistent dyslipidaemia, could modify its levels. We undertook the present study to examine the serum Lp(a) concentration in various dyslipidaemias and to reveal any correlation of serum Lp(a) concentration with the other lipid parameters in a large group of dyslipidaemic Greek patients. A total of 242 patients followed as outpatients in our lipid clinic were studied. The patients were stratified into four main groups. Patients with cholesterol levels greater than 5.17 mmol/L but normal triglycerides were regarded as hypercholesterolaemic (n=85), patients with triglycerides greater than 2.25 mmol/L but normal cholesterol levels as hypertriglyceridaemic (n=51), patients with both increased cholesterol and triglyceride levels as having mixed hyperlipidaemia (n=62), and finally patients with decreased (<0.90 mmol/L) high-density lipoprotein (HDL) cholesterol but normal cholesterol and triglyceride levels as having primary hypoalphalipoproteinaemia (n=44). Hypercholesterolaemic patients exhibited the highest serum Lp(a) levels, while hypertriglyceridaemic patients exhibited the lowest. Patients with mixed hyperlipidaemia had intermediate serum Lp(a) concentration, which was significantly higher than that of hypertriglyceridaemic patients but significantly lower than that of hypercholesterolaemic patients. Interestingly, patients with low serum HDL-cholesterol levels presented with low serum Lp(a) concentration similar to that of hypertriglyceridaemic patients. In hypercholesterolaemic patients no correlation was found between serum total and low-density lipoprotein (LDL) cholesterol nor apolipoprotein B (apoB) levels and Lp(a) concentration. On the contrary, in hypertriglyceridaemic patients an inverse correlation was observed between serum triglycerides and Lp(a) concentration. After dividing the hypertriglyceridaemic patients into one group with elevated (>1.3 g/L) serum apoB levels (n=32) and another group with normal apoB levels (n=19), we found that the median serum Lp(a) concentration was three times higher in hyperapoB patients compared to patients with normal apoB levels. We conclude that serum Lp(a) levels are different in various types of primary hyperlipidaemia and are modulated according to the type of lipid elevation.


Characterization of a Dispiroketal Spirolide Subclass from Alexandrium ostenfeldii.
A new subclass of spirolide marine toxins, represented by spirolides H (1) and I (2), were isolated from the marine dinoflagellate Alexandrium ostenfeldii. Spirolides H and I are structurally distinct from other spirolides in that they contain a 5:6 dispiroketal ring system rather than the trispiroketal ring system characteristic of previously isolated spirolides. The structures were assigned using a combination of spectrometric and spectroscopic techniques. Previously isolated spirolides containing a cyclic imine moiety showed toxicity in the mouse bioassay. Spirolide H contains this cyclic imine moiety but does not show toxicity in the mouse assay, suggesting that the presence of the cyclic imine moiety is not the only structural requirement for toxicity.


Ethanol and protein metabolism.
This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Carol C. Cunningham and Victor R. Preedy. The presentations were (1) Ribosomal content, ribosomal localization and the levels of ribosomal protein mRNA and rRNA in rat skeletal muscle exposed to ethanol, by Alistair G. Paice, John E. Hesketh, Timothy J. Peters, and Victor R. Preedy; (2) Altered hepatic mitochondrial ribosome structure after chronic ethanol administration, by Vinood B. Patel and Carol C. Cunningham; (3) Clinical aspects of hepatic protein metabolism and alcohol, by Elena Volpi; and (4) Effects of oral intake of alanine plus glutamine on ethanol metabolism and ethanol-related depression in motor activity, by Kazunori Mawatari, H. Masaki, M. Mori, and Kunio Torii.


Play or learn: European-American and Chinese kindergartners' perceptions about the conflict.
Kindergarten is the age at which children's future time perspective emerges. This capacity enables them to form goals based on past and ongoing experiences and project themselves in the future. This development may play an important role in guiding children in self-regulated learning. When faced with the conflict between their need to learn and their desire to play (CLP), children make choices based on their perceptions of CLP. However, their CLP-related perceptions and responses are also influenced by the values their culture upholds. Research shows that Western learning emphasizes more mental activities and positive affect, whereas East Asian learning stresses more social/moral self-perfection. Children's CLP-related perceptions and responses are likely shaped by their respective cultures' values. This study examined kindergartners' emergent perceptions of and responses to CLP. Both commonalities and possible cultural differences were investigated. The sample was 130 middle-class European-American and Chinese kindergartners, balanced for culture and gender. Children each heard a story beginning with a picture of a protagonist who is practicing words at home but hears children playing outside. Children were asked to complete the story and were probed further when they mentioned ideas related to learning and play. All interviews were audio-recorded and transcribed for coding. Tests were conducted for group differences. Most children from both groups identified CLP and shared similar views about their need to complete schoolwork, benefits of learning, negativity of neglecting learning, and ways to resist temptation to play. However, large cultural differences also emerged. Chinese children showed greater awareness of CLP and expressed more positive regard for learning, learning virtues, and receptivity to adult expectations.


Novel ultrasound-based volume estimation of prostatic benign enlargement to improve decision-making on surgical approach.
To assess the precision of preoperative ultrasonography (US)-determined prostate volume and to propose formulas for improving it. This retrospective study comprised 155 consecutive men who underwent open prostatectomy for benign prostatic hyperplasia (BPH) between 2013 and 2019. Preoperative prostate volume was estimated by either abdominal US (AUS) (n = 92) or transrectal US (TRUS) (n = 63), and was compared with the weight of surgically enucleated tissue at a conversion rate of 1 ml (US) = 1 g tissue. Statistical analysis was conducted and a novel formula for prostate volume was constructed. The median prostate volumes by AUS and TRUS were 140 ml [interquartile ratio (IQR) 111-182] and 108 ml (IQR 93-120), respectively. Enucleated tissue weight was lower than the AUS assessment by a median difference of 50 g (IQR 28.7-75.7; p < 0.001), and lower than the TRUS assessment by a median difference of 27 g, IQR 10-43, p < 0.001). Using a cutoff of 80 ml, 30 (33%) AUS patients and 23 (36%) TRUS patients underwent unneeded open procedures. Mathematical calculations revealed two formulas that significantly adjusted for the actual weight: 1.082*Age + 0.523*AUS - 53.845 for AUS and 0.138*age + 2.22*prostate-specific antigen + 0.453*TRUS + 11.682 for TRUS (p < 0.001). These formulas increased the overall US prostate volume accuracy from 65% to 85%. Assessment of prostate volume by US is imprecise for decision-making of whether to perform open simple prostatectomy for BPH. Our novel formulas may enhance stratification of patients with prostatic enlargement to a more optimal surgical approach. Future studies in larger cohorts are needed to substantiate our results.


Association of maternal exposures with adiposity at age 4/5 years in white British and Pakistani children: findings from the Born in Bradford study.
There is evidence that, from birth, South Asians are fatter, for a given body mass, than Europeans. The role of developmental overnutrition related to maternal adiposity and circulating glucose in these ethnic differences is unclear. Our aim was to compare associations of maternal gestational adiposity and glucose with adiposity at age 4/5 years in white British and Pakistani children. Born in Bradford is a prospective study of children born between 2007 and 2010 in Bradford, UK. Mothers completed an OGTT at 27-28 weeks of gestation. We examined associations between maternal gestational BMI, fasting glucose, post-load glucose and diabetes (GDM) and offspring height, weight, BMI and subscapular skinfold (SSF) and triceps skinfold (TSF) thickness at age 4/5 years, using data from 6060 mother-offspring pairs (2717 [44.8%] white British and 3343 [55.2%] Pakistani). Pakistani mothers had lower BMI and higher fasting and post-load glucose and were twice as likely to have GDM (defined using modified WHO criteria) than white British women (15.8% vs 6.9%). Pakistani children were taller and had lower BMI than white British children; they had similar SSF and lower TSF. Maternal BMI was positively associated with the adiposity of offspring in both ethnic groups, with some evidence of stronger associations in Pakistani mother-offspring pairs. For example, the difference in adjusted mean BMI per 1 kg/m2 greater maternal BMI was 0.07 kg/m2 (95% CI 0.05, 0.08) and 0.10 kg/m2 (95% CI 0.09. 0.11) in white British and Pakistani children, respectively, with equivalent results for SSF being 0.07 mm (95% CI 0.05, 0.08) and 0.09 mm (95% CI 0.08. 0.11) (p for ethnic difference < 0.03 for both). There was no strong evidence of association of fasting and post-load glucose, or GDM, with outcomes in either group. At age 4/5 years, Pakistani children are taller and lighter than white British children. While maternal BMI is positively associated with offspring adiposity, gestational glycaemia is not clearly related to offspring adiposity in either ethnic group.


Atmospheric scattering for varying degrees of saturation and turbulent intermittency.
Atmospheric turbulence is inherently inhomogeneous and intermittent. Short periods of high activity are embedded in longer periods of relative calm. Local spatial and temporal changes in sound speed associated with this intermittency increase the likelihood of measuring large values of scattered acoustic signals. Previous work successfully predicted the probability density functions (pdf's) of fully saturated, scattered signals measured within an acoustic shadow zone [Wilson et al., J. Acoust. Soc. Am. 99, 3393-3400 (1996)]. The more general case of incompletely saturated scattering is considered in this paper; using the Rice-Nagakami distribution a theory is developed. The predicted intensity pdf has two free parameters: one to describe the degree of intermittency and a second for the degree of saturation. For validation purposes, outdoor propagation measurements were made over a flat, hard ground at ranges of 146-283 m and at frequencies of 50-540 Hz. The saturation parameter was determined from the acoustic data and also estimated from the turbulence conditions. The degree of saturation increased with frequency, and measured intensity pdf's were found to be in excellent agreement with the theory.


Trends in wait-list mortality in children listed for heart transplantation in the United States: era effect across racial/ethnic groups.
We sought to evaluate trends in overall and race-specific pediatric heart transplant (HT) wait-list mortality in the United States (US) during the last 20 years. We identified all children <18 years old listed for primary HT in the US during 1989-2009 (N = 8096, 62% White, 19% Black, 13% Hispanic and 6% Other) using the Organ Procurement and Transplant Network database. Wait-list mortality was assessed in four successive eras (1989-1994, 1995-1999, 2000-2004 and 2005-2009). Overall wait-list mortality declined in successive eras (26%, 23%, 18% and 13%, respectively). The decline across eras remained significant in adjusted analysis (hazard ratio [HR] 0.70 in successive eras, 95% confidence interval [CI], 0.67-0.74) and was 67% lower for children listed during 2005-2009 versus those listed during 1989-1994 (HR 0.33; CI, 0.28-0.39). In models stratified by race, wait-list mortality decreased in all racial groups in successive eras. In models stratified by era, minority children were not at higher risk of wait-list mortality in the most recent era. We conclude that the risk of wait-list mortality among US children listed for HT has decreased by two-thirds during the last 20 years. Racial gaps in wait-list mortality present variably in the past are not present in the current era.


Injectable Versus Oral First-Line Disease-Modifying Therapies: Results from the Italian MS Register.
The current study aims to compare injectable and oral first-line disease-modifying therapies (DMTs) for time to first relapse, time to confirmed disability progression (CDP), and time to discontinuation using a cohort of relapsing remitting multiple sclerosis (RRMS) patients, with data extracted from the Italian MS Register. This multicenter, observational, retrospectively acquired, and propensity-adjusted cohort study utilized RRMS-naïve patients from the Italian MS Register who started either injectable or oral first-line DMTs between January 1, 2010, and December 31, 2017, to evaluate the impact on disability outcomes in patients. Enrolled patients were divided into two groups, namely the injectable group (IG) and the oral group (OG). Of a cohort of 11,416 patients, 4602 were enrolled (3919 in the IG and 683 in the OG). The IG had a higher rate of women (67.3% vs 63.4%, p < 0.05) and a lower mean age (36.1 ± 10.9 vs 38.9 ± 11.8, p < 0.001). The event time to first relapse demonstrated a lower risk in the OG (HR = 0.58; CI 95% 0.48-0.72, p < 0.001). However, no differences were found between the two groups with respect to the risk of CDP (HR = 0.94; CI 95% 0.76-1.29, p = 0.941), while a lower risk of DMT was found in the OG (HR = 0.72; CI 95% 0.58-0.88, p = 0.002) for the event time to discontinuation. Real-world data from the Italian MS Register suggests that first-line oral DMTs are associated with a lower risk of experiencing a new relapse and of therapy discontinuation compared to injectable DMTs.


P53-dependent antiproliferative and pro-apoptotic effects of trichostatin A (TSA) in glioblastoma cells.
Glioblastomas are known to be highly chemoresistant, but HDAC inhibitors (HDACi) have been shown to be of therapeutic relevance for this aggressive tumor type. We treated U87 glioblastoma cells with trichostatin A (TSA) to define potential epigenetic targets for HDACi-mediated antitumor effects. Using a cDNA array analysis covering 96 cell cycle genes, cyclin-dependent kinase inhibitor p21(WAF1) was identified as the major player in TSA-induced cell cycle arrest. TSA slightly inhibited proliferation and viability of U87 cells, cumulating in a G1/S cell cycle arrest. This effect was accompanied by a significant up-regulation of p53 and its transcriptional target p21(WAF1) and by down-regulation of key G1/S regulators, such as cdk4, cdk6, and cyclin D1. Nevertheless, TSA did not induce apoptosis in U87 cells. As expected, TSA promoted the accumulation of total acetylated histones H3 and H4 and a decrease in endogenous HDAC activity. Characterizing the chromatin modulation around the p21(WAF1) promoter after TSA treatment using chromatin immunoprecipitation, we found (1) a release of HDAC1, (2) an increase of acetylated H4 binding, and (3) enhanced recruitment of p53. p53-depleted U87 cells showed an abrogation of the G1/S arrest and re-entered the cell cycle. Immunofluorescence staining revealed that TSA induced the nuclear translocation of p21(WAF1) verifying a cell cycle arrest. On the other hand, a significant portion of p21(WAF1) was present in the cytoplasmic compartment causing apoptosis resistance. Furthermore, TSA-treated p53-mutant cell line U138 failed to show an induction in p21(WAF1), showed a deficient G2/M checkpoint, and underwent mitotic catastrophe. We suggest that HDAC inhibition in combination with other clinically used drugs may be considered an effective strategy to overcome chemoresistance in glioblastoma cells.


Arabidopsis TT19 functions as a carrier to transport anthocyanin from the cytosol to tonoplasts.
Anthocyanins are synthesized in the cytosolic surface of the endoplasmic reticulum (ER) but dominantly accumulate in the vacuole. Little is known about how anthocyanins are transported from the ER to the vacuole. Here, we provide evidence supporting that Transparent Testa 19 (TT19), a glutathione S-transferase (GST), functions as a carrier to transport cyanidin and/or anthocyanins to the tonoplast. We identified a novel tt19 mutant (tt19-7), which barely accumulates anthocyanins but produces a 36% higher level of flavonol than the wild-type (WT), from ethyl methanesulfonate mutagenized seeds. Expressing TT19-fused green fluorescence protein (GFP) in tt19-7 rescues the mutant phenotype in defective anthocyanin biosynthesis, indicating that TT19-GFP is functional. We further showed that TT19-GFP is localized not only in the cytoplasm and nuclei, but also on the tonoplast. The membrane localization of TT19-GFP was further ascertained by immunoblot analysis. In vitro assay showed that the purified recombinant TT19 increases water solubility of cyanidin (Cya) and cyanidin-3-O-glycoside (C3G). Compared with C3G, Cya can dramatically quench the intrinsic tryptophan fluorescence of TT19 to much lower levels, indicating a higher affinity of TT19 to Cya than to C3G. Isothermal titration calorimetry analysis also confirmed physical interaction between TT19 and C3G. Taken together, our data reveal molecular mechanism underlying TT19-mediated anthocyanin transportation.


Generation of primary tumors with Flp recombinase in FRT-flanked p53 mice.
The site-specific recombinases Cre and Flp can mutate genes in a spatially and temporally restricted manner in mice. Conditional recombination of the tumor suppressor gene p53 using the Cre-loxP system has led to the development of multiple genetically engineered mouse models of human cancer. However, the use of Cre recombinase to initiate tumors in mouse models limits the utilization of Cre to genetically modify other genes in tumor stromal cells in these models. To overcome this limitation, we inserted FRT (flippase recognition target) sites flanking exons 2-6 of the endogenous p53 gene in mice to generate a p53(FRT) allele that can be deleted by Flp recombinase. We show that FlpO-mediated deletion of p53 in mouse embryonic fibroblasts impairs the p53-dependent response to genotoxic stress in vitro. In addition, using FSF-Kras(G12D/+); p53(FRT/FRT) mice, we demonstrate that an adenovirus expressing FlpO recombinase can initiate primary lung cancers and sarcomas in mice. p53(FRT) mice will enable dual recombinase technology to study cancer biology because Cre is available to modify genes specifically in stromal cells to investigate their role in tumor development, progression and response to therapy.


Neurobehavioral effects of permethrin are associated with alterations in regional levels of biogenic amine metabolites and amino acid neurotransmitters.
Oral administration of 120 or 240 mg/kg permethrin produced dose- and time-related tremor in rats with the peak effect occurring 5 hrs after dosing. Subsequent experiments done 5 hrs postdosing found that 45 to 180 mg/kg permethrin produced dose-related increases in rectal temperature and enhanced responsiveness to an acoustic stimulus. Tremor was detected at 90 and 180 mg/kg. Neurochemical analyses of regional biogenic amines and their metabolites and amino acids 5 hrs after 90 or 180 mg/kg indicated that 5-HIAA levels were increased in the hypothalamus (HYP), brain stem (BS), hippocampus (HPC), and striatum (STR); 5-HT was not affected. MHPG was increased in the HYP and BS, while NE was decreased at the high dose only. DOPAC and HVA were increased in the STR after 90 and 180 mg/kg, while DA was not affected. Aspartate levels were increased in the BS and STR; glutamate was increased in the BS. Taurine, glutamine, glycine, and GABA were not affected. A time-course analysis of neurochemical changes 2, 5, 12, and 24 hrs postdosing indicated that 5 hrs was the time of peak effect for permethrin. Permethrin-induced tremor and hyperthermia were significantly correlated with dose- and time-related changes in MHPG, 5-HIAA, and ASP.


Effect of Altering Dietary n-6:n-3 Polyunsaturated Fatty Acid Ratio with Plant and Marine-Based Supplement on Biomarkers of Bone Turnover in Healthy Adults.
Although there is accumulating evidence for a protective role of n-3 polyunsaturated fatty acids (n-3 PUFAs) on bone health, there are limited studies that examine the effect of altering dietary n-6:n-3 PUFA ratio with plant and marine sources of n-3 PUFA on bone health. Healthy adults (n = 24) were randomized into an eight-week crossover study with a four-week washout between treatments, with each subject consuming three of four diets. The four diets differed in the dietary n-6:n-3 PUFA ratios and either had an algal oil supplement added or not: (Control diet (10:1); α-linolenic acid (ALA) diet (2:1); Eicosapentaenoic acid/Docosahexaenoic acid (EPA/DHA) diet (10:1 plus supplement (S) containing EPA/DHA; Combination diet (2:1 + S)). The supplement was microalgae oil that provided 1 g EPA + DHA/day. Flaxseed oil and walnuts provided 8.6 g of ALA/day in the 2:1 diets. Serum levels of c-telopeptide (CTX), procollagen Type I N-terminal peptide, and osteocalcin showed significant correlation with age but none of the bone markers or peroxisomal proliferator-activated receptor-γ mRNA expression was significantly different between the diets. Serum CTX was negatively associated with red blood cell membrane linoleic acid and ALA and positively associated with membrane DHA. Neither altering dietary n-6:n-3 PUFA ratio from a 10:1 to a 2:1 ratio nor adding EPA/DHA supplement significantly changed bone turnover in the short term in healthy adults.


Junin virus infects mouse cells and induces innate immune responses.
Junín virus is the causative agent for Argentine hemorrhagic fever, and its natural host is the New World rodent Calomys musculinus. The virus is transmitted to humans by aerosolization, and it is believed that many of the clinical symptoms are caused by cytokines produced by sentinel cells of the immune system. Here we used the Junín virus vaccine strain Candid 1 to determine whether mouse cells could be used to study virus entry and antiviral innate immune responses. We show that Candid 1 can infect and propagate in different mouse-derived cell lines through a low-pH-dependent, transferrin receptor 1-independent mechanism, suggesting that there is a second entry receptor. In addition, Candid 1 induced expression of the antiviral cytokines tumor necrosis factor alpha and beta interferon in macrophages, and this induction was independent of viral replication. Using Candid 1, as well as virus-like particles bearing the viral glycoprotein, to infect different primary cells and established macrophage cell lines with deletions in the Toll-like receptor (TLR) pathway, we show that TLR2 is a cellular sensor of both the Parodi and Candid 1 viral glycoproteins. Because Junín virus is highly lethal in humans, the use of an experimentally tractable model system, such as the mouse, could provide a better understanding of the antiviral innate cellular responses to Junín virus and the role of these responses in pathogenesis.


Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung.
Among alternative therapeutic strategies in clinically aggressive neuroendocrine tumors (NETs) of the lung, promising results have been obtained in experimental clinical trials with mammalian target of rapamycin (mTOR) inhibitors, though in the absence of a proven mTOR signaling activation status. This study analyzed the expression of phosphorylated mTOR (p-mTOR) and its major targets, the ribosomal p70S6-kinase (S6K) and the eukaryotic initiation factor 4E-binding protein 1 (4EBP1) in a large series of 218 surgically resected, malignant lung NETs, including 24 metastasizing typical carcinoids, 73 atypical carcinoids, 60 large cell neuroendocrine carcinomas (LCNECs), and 61 small cell carcinomas (SCLCs). By immunohistochemistry, low-to-intermediate-grade tumors as compared with high-grade tumors showed higher levels of p-mTOR and phosphorylated S6K (p-S6K) (P<0.001), at variance with phosphorylated 4EBP1 (p-4EBP1), which was mainly expressed in LCNECs and SCLCs (P<0.001). The activated status of mTOR pathway was proved by the strong correlation of p-mTOR with p-S6K and somatostatin receptor(s). Western blot analysis of NET tumor samples confirmed such findings, and differential sensitivity to mTOR inhibition according to mTOR pathway activation characteristics was determined in two lung carcinoid cell lines in vitro. None of the investigated molecules had an impact on survival. However, in low-grade tumors, low p-mTOR expression correlated with lymph node metastases (P=0.016), recurrent disease, and survival (P=0.005). In conclusion, these data demonstrate a differential mTOR activation status in the spectrum of pulmonary NETs, possibly suggesting that mTOR pathway profiling might play a predictive role in candidate patients for mTOR-targeted therapies.


Anhydrides-Cured Bimodal Rubber-Like Epoxy Asphalt Composites: From Thermosetting to Quasi-Thermosetting.
The present engineering practices show the potential that epoxy asphalt composites (EACs) would be a better choice to obtain long life for busy roads. To understand the service performance⁻related thermorheological properties of prepared bimodal anhydrides-cured rubber-like EACs (REACs), a direct tensile tester, dynamic shear rheometer and mathematical model were used. Tensile tests demonstrate that all the REACs reported here are more flexible than previously reported anhydrides-cured REACs at both 20 and 0 °C. The better flexibility is attributed to the change of bimodal networks, in which cross-linked short chains decreased and cross-linked long chains increased, relatively. Strain sweeps show that all the REACs have linear viscoelastic (LVE) properties when their strains are smaller than 1.0% from -35 to 120 °C. Temperature sweeps illustrate that the thermorheological properties of REACs evolve from thermosetting to quasi-thermosetting with asphalt content, and all the REACs retain solid state and show elastic properties in the experimental temperature range. A Cole⁻Cole plot and Black diagram indicate that all the REACs are thermorheologically simple materials, and the master curves were constructed and well-fitted by the Generalized Logistic Sigmoidal models. This research provides a facile approach to tune the thermorheological properties of the REACs, and the cheaper quasi-thermosetting REAC facilitates their advanced applications.


Radiographic Follow-up of DDH in Infants: Are X-rays Necessary After a Normalized Ultrasound?
Concerns about radiation exposure have created a controversy over long-term radiographic follow-up of developmental dysplasia of the hip (DDH) in infants who achieve normal clinical and ultrasonographic examinations. The purpose of this study was to assess the importance of continued radiographic monitoring by contrasting the incidence of residual radiographic dysplasia to the risks of radiation exposure. We reviewed a consecutive series of infants with idiopathic DDH presenting to our institution over 4 years. Infants with "normalized DDH" had achieved a stable clinical examination with an ultrasound revealing no signs of either hip instability or acetabular dysplasia. We excluded infants with persistently abnormal ultrasonographic indices, clinical examinations, or both by 6 months of age, including those requiring surgical reduction. Anteroposterior pelvic radiographs at approximately 6 and 12 months of age were then evaluated for evidence of residual radiographic acetabular dysplasia. Radiation effective dose was calculated using PCXMC software. We identified 115 infants with DDH who had achieved both normal ultrasonographic and clinical examinations at 3.1±1.1 months of age. At the age of 6.6±0.8 months, 17% of all infants demonstrated radiographic signs of acetabular dysplasia. Of infants left untreated (n=106), 33% had dysplasia on subsequent radiographs at 12.5±1.2 months of age. No significant differences were evident in either the 6- or 12-month rates of dysplasia between infants successfully treated with a Pavlik harness and infants normalizing without treatment but with a history of risk factors (P>0.05). The radiation effective dose was <0.01 mSv for the combined 6- and 12-month single-view anteroposterior radiographs of the pelvis. The notable incidences of radiographic dysplasia after previous DDH normalization in our study cohort appear to outweigh the risks of radiation exposure. Our findings may warrant radiographic follow-up in this population of infants through at least walking age to allow timely diagnosis and early intervention of residual acetabular dysplasia. Level IV-retrospective case series.


The dispersed cell culture as model for functional studies of the subcommissural organ: preparation and characterization of the culture system.
The subcommissural organ (SCO) is an enigmatic secretory gland of the brain, which is believed to be derived from ependymal (glial) precursor cells. We here developed a dispersed cell culture system of the bovine SCO as an approach to functional analyses of this brain gland. Tissue of the bovine SCO obtained from the slaughterhouse was papain dissociated either directly after dissection or after preparation of SCO explants. The latter had been maintained for 4-6 weeks in organ culture. The dispersed cells were cultured for up to 14 days and continuously tested for their secretory state by immunostaining of their secretory product. With respect to the morphology of the SCO cells (shape, processes, nucleus), no difference was found between the culture of freshly dissociated SCOs and that of dissociated SCO explants. In all cases, the dissociation caused a dedifferentiation; typical elongated cells were formed increasingly after 1 day of culture. Thereafter, only the cellular size increased, whereas the shape and the viability of the cells remained unchanged. Proliferating SCO cells were never observed. The culture obtained from fresh SCO tissue contained more glia cells and fibrocytes than the culture prepared from SCO explants. The proliferation of glia cells and fibrocytes was suppressed by blocking the mitotic activity with cytosine-beta-D-arabino furanoside (CAF). The cytophysiological features of the cultured dispersed cells of both origins did not differ as demonstrated by classical histology, by immunocytochemistry for the secretory products of the SCO, by the characteristics of calcium influx into the cytoplasm ([Ca2+]i) and cyclic adenosine monophosphate (cAMP) after stimulation with adenosine-5-triphosphate, substance P or serotonin, and by the activation of the transcription factor cAMP-responsive element-binding protein. Because of the maintenance of their viability, their capacity to release the secretory product into the culture medium, their receptive capacity, and their signal transduction pathways, we conclude that the dispersed cell culture system, especially that obtained from SCO explants, represents an appropriate and useful model for functional studies of the mammalian SCO.


Brain and muscle express a unique alternative transcript of alphaII spectrin.
Alternative splicing of pre-mRNA transcripts of alpha and beta spectrin has emerged as an important generator of diversity in this gene family, yet the functional consequences and extent of this diversity remains unknown. We have cloned and characterized full-length alphaII spectrin cDNA from human fetal brain (GenBank and ). On the basis of the predicted amino acid sequence, 11 amino acid substitutions, presumably representing polymorphisms, have been identified that distinguish this alphaII spectrin from human lung fibroblast alphaII spectrin. In addition, human fetal brain spectrin displays a novel five amino acid insertion in repeat 15 that arises from alternative mRNA splicing and that distinguishes this spectrin from lung fibroblast alphaII++ spectrin. This discovery, together with two previously identified regions of alternative mRNA splicing in alphaII spectrin suggest that as many as eight different splice forms of the mature protein might exist if all combinations (at inserts 1, 2, and 3) of alternative mRNA splicing are utilized. To assess this possibility, the tissue distribution of alternative exon usage was investigated by semiquantitative PCR with intron-jumping primer sets. Tissues examined were from mouse and included heart, kidney, lung, liver, thymus, spleen, brain, ovary, testis, and skeletal muscle, as well as mouse embryonic tissue. Transcripts both with and without insert 1, representing a 60 bp insertion within alphaII spectrin repeat 10, were identified in all tissues. In contrast, transcripts with insert 2, the novel 15 bp insertion reported here, were only expressed in brain, heart, skeletal muscle, and embryonic tissue. In all tissues examined only transcripts positive for insert 3, an 18 bp insertion in repeat 21, were amplified, even under conditions in which a 30% level of insert 3 negative transcript could be easily detected in artificially prepared control samples. All combinations of insert 1 and insert 2 were identified together in individual transcripts, verifying at least four distinct isoforms of alphaII spectrin. These have been named alphaIISigma1 through alphaIISigma4, in accord with current spectrin naming conventions. Dynamic molecular modeling of the 15th repeat unit incorporating insert 2 predicts that the spliced sequence forms a loop between helices A and B, and suggests that this insert might constitute a novel protein interaction site. The presence of this sequence in alphaIISigma3 and alphaIISigma4 spectrin suggests a specialized and heretofore unanticipated function for the 15th repeat of this molecule.


Are Twenty-Four Sessions of Aerobic Exercise Sufficient for Improving Cardiac Parameters in Diabetes Mellitus? A Randomized Controlled Trial.
Background: Diabetes is a chronic disease that reduces cardiorespiratory fitness and increases systolic and diastolic blood pressures as well as resting heart rate due to the activity level of the sympathetic nervous system. The aim of this study was to assess the effectiveness of 2 types of aerobic exercise, with and without external loading, on cardiac parameters in diabetic patients. Methods: This randomized controlled trial was carried out on 45 volunteers. These individuals were randomly divided into aerobic, weighted vest, and control groups. The aerobic protocol comprised 24 sessions of aerobic exercise. The exercise program for the weighted vest group was identical to that of the aerobic group, except that the subjects wore a weighted vest. The parameters were measured before and after the 24 sessions. Results: The mean age of the study population was 48.30±5.02 years in the aerobic group, 48.33±5.74 years in the weighted vest group, and 48.60±4.79 years in the control group. Males comprised 7 (53.8%) patients in the aerobic group, 7 (58.3%) in the weighted vest group, and 8 (53.3%) in the control group. After 8 weeks, maximum oxygen consumption in the aerobic group (mean±SD=37.54±8.02 mL/kg/min, 95% CI: 5.48 to 11.60; P<0.001) and the weighted vest group (mean±SD=35.92±3.96 mL/kg/min, 95% CI: 4.36 to 9.64; P<0.001) was increased, similar to metabolic equivalent of task in the aerobic group (mean±SD=11.60±1.62 kcal/kg×h, 95% CI: 1.48 to 2.72; P<0.001) and the weighted vest group (mean±SD=11.21±1.11 kcal/kg×h, 95% CI: 1.23 to 2.28; P<0.001). Furthermore, resting heart rate decreased significantly in the aerobic group (mean ± SD=90.23±8.90 bpm, 95% CI: -13.93 to -1.29; P=0.022) and the weighted vest group (mean±SD=90.58±9.19 bpm, 95% CI: -0.16 to - 12.33; P=0.045). Conclusion: These findings suggest that 24 aerobic exercise sessions might improve cardiac parameters in type 2 diabetes.


Prevalence of depression and depressive symptoms among outpatients: a systematic review and meta-analysis.
Depression and depressive symptoms are common mental disorders that have a considerable effect on patients' health-related quality of life and satisfaction with medical care, but the prevalence of these conditions varies substantially between published studies. The aim of this study is to conduct a systematic review and meta-analysis to provide a precise estimate of the prevalence of depression or depressive symptoms among outpatients in different clinical specialties. Systematic review and meta-analysis. The PubMed and PsycINFO, EMBASE and Cochrane Library databases were searched to identify observational studies that contained information on the prevalence of depression and depressive symptoms in outpatients. All studies included were published before January 2016. Data characteristics were extracted independently by two investigators. The point prevalence of depression or depressive symptoms was measured using validated self-report questionnaires or structured interviews. Assessments were pooled using a random-effects model. Differences in study-level characteristics were estimated by meta-regression analysis. Heterogeneity was assessed using standard χ2 tests and the I2 statistic. The study protocol has been registered with PROSPERO under number CRD42017054738. Eighty-three cross-sectional studies involving 41 344 individuals were included in this study. The overall pooled prevalence of depression or depressive symptoms was 27.0% (10 943/41 344 individuals; 95% CI 24.0% to 29.0%), with significant heterogeneity between studies (p<0.0001, τ2=0.3742, I2=96.7%). Notably, a significantly higher prevalence of depression and depressive symptoms was observed in outpatients than in the healthy controls (OR 3.16, 95% CI 2.66 to 3.76, I2=72.0%, χ 2 =25.33). The highest depression/depressive symptom prevalence estimates occurred in studies of outpatients from otolaryngology clinics (53.0%), followed by dermatology clinics (39.0%) and neurology clinics (35.0%). Subgroup analyses showed that the prevalence of depression and depressive symptoms in different specialties varied from 17.0% to 53.0%. The prevalence of depression and depressive symptoms was higher among outpatients in developing countries than in outpatients from developed countries. Moreover, the prevalence of depression and depressive symptoms in outpatients slightly decreased from 1996 to 2010. Regarding screening instruments, the Beck Depression Inventory led to a higher estimate of the prevalence of depression and depressive symptoms (1316/4702, 36.0%, 95% CI 29.0% to 44.0%, I2=94.8%) than the Hospital Anxiety and Depression Scale (1003/2025, 22.0%, 95% CI 12.0% to 35.0%, I2=96.6%). Our study provides evidence that a significant proportion of outpatients experience depression or depressive symptoms, highlighting the importance of developing effective management strategies for the early identification and treatment of these conditions among outpatients in clinical practice. The substantial heterogeneity between studies was not fully explained by the variables examined.


Niche, not phylogeny, governs the response to oxygen availability among diverse Pseudomonas aeruginosa strains.
Pseudomonas aeruginosa, a ubiquitous opportunistic pathogen, is a leading cause of chronic infection of airways in cystic fibrosis (CF) patients. Chronic infections typically arise from colonization by environmental strains, followed by adaptation of P. aeruginosa to the conditions within the CF airway. It has been suggested that oxygen availability can be an important source of selection causing trait changes associated with the transition to chronic infection, but little data exist on the response of P. aeruginosa to varying levels of oxygen. Here, we use a diverse collection of P. aeruginosa strains recovered from both CF patients and environmental sources to evaluate the role of oxygen availability in driving adaptation to the CF lung while also accounting for phylogenetic relatedness. While we can detect a signal of phylogeny in trait responses to oxygen availability, niche of origin is a far stronger predictor. Specifically, strains isolated from the lungs of CF patients are more sensitive to external oxidative stress but more resistant to antibiotics under anoxic conditions. Additionally, many, though not all, patho-adaptive traits we assayed are insensitive to oxygen availability. Our results suggest that inferences about trait expression, especially those associated with the transition to chronic infection, depend on both the available oxygen and niche of origin of the strains being studied.


Strongyloidiasis and other intestinal nematode infections.
In contrast to other helminthic parasites, Strongyloides stercoralis can replicate within humans, causing a chronic persistent infection that can be severe and fatal in compromised hosts. This article reviews new developments to help meet the clinical challenges of this infection, including clinical clues to the diagnosis, new diagnostic methods, including stool culture and serological assays, new drugs such as albendazole and ivermectin, and difficult treatment issues. The other major intestinal nematode parasites, including Ascaris, hookworm, and Trichuris, are extremely common worldwide, but in North America their clinical presentation is often more subtly related to low-grade worm burdens or allergic manifestations. Special consideration is given to difficult management issues, including the patient with unexplained eosinophilia, the pregnant patient, and the patient who passes a worm.