Synaptic plasticity and NO-cGMP-PKG signaling coordinately regulate ERK-driven gene expression in the lateral amygdala and in the auditory thalamus following Pavlovian fear conditioning.
We have recently hypothesized that NO-cGMP-PKG signaling in the lateral nucleus of the amygdala (LA) during auditory fear conditioning coordinately regulates ERK-driven transcriptional changes in both auditory thalamic (MGm/PIN) and LA neurons that serve to promote pre- and postsynaptic alterations at thalamo-LA synapses, respectively. In the present series of experiments, we show that N-methyl-D-aspartate receptor (NMDAR)-driven synaptic plasticity and NO-cGMP-PKG signaling in the LA regulate the training-induced expression of ERK and the ERK-driven immediate early genes (IEGs) Arc/Arg3.1, c-Fos, and EGR-1 in the LA and the MGm/PIN. Rats receiving intra-LA infusion of the NR2B selective antagonist Ifenprodil, the NOS inhibitor 7-Ni, or the PKG inhibitor Rp-8-Br-PET-cGMPS exhibited significant decreases in ERK activation and in the training-induced expression of all three IEGs in the LA and MGm/PIN while intra-LA infusion of the PKG activator 8-Br-cGMP had the opposite effect. Remarkably, those rats given intra-LA infusion of the membrane impermeable NO scavenger c-PTIO exhibited significant decreases in ERK activation and ERK-driven IEG expression in the MGm/PIN, but not in the LA. Together with our previous experiments, these results suggest that synaptic plasticity and the NO-cGMP-PKG signaling pathway promote fear memory consolidation, in part, by regulating ERK-driven transcription in both the LA and the MGm/PIN. They further suggest that synaptic plasticity in the LA during fear conditioning promotes ERK-driven transcription in MGm/PIN neurons via NO-driven "retrograde signaling."


The epidemiology of eating disorder behaviors: an Australian community-based survey.
The study aims were to evaluate the prevalence and distribution of respective eating disorder behaviors (DSM-IV criteria) in a representative community-based sample. Data were obtained from 3,001 interviews of a randomly selected sample of 4,200 individuals' (age > 15 years) households in South Australia. Ninety-six (3.2%) of respondents had regular current episodes of binge eating, 48 (1.6%) regularly fasted or used strict dieting, 24 (0.8%) purged. An estimated 8 (0.3%) had bulimia nervosa and 30 (1%) had binge eating disorder. Binge eating and dieting were most common in people who were in their early to mid thirties. Dieting and purging, but not regular binge eating, were more common in women than in men. Purging was most common in the 35-44 year age range. The only behavior significantly associated with (increased) weight was binge eating. Unmarried subjects were less likely to diet than married subjects. No significant differences in rates of these behaviors were found for household income. Problematic eating disorder behaviors in older women and in men were more common than expected and merit further clinical and research attention.


Hydrolysis of Corn Stover by Talaromyces cellulolyticus Enzymes: Evaluation of the Residual Enzymes Activities Through the Process.
The obtainment of sugars from lignocellulosic residues represents a sustainable and versatile platform for the production of a number of bio-based products. Cellulases are a family of enzymes which can effectively hydrolyze the biomass polysaccharides at mild conditions. Cellulolytic fungi belonging to the genera Trichoderma and Aspergillus are the most commonly source of commercial cellulases used so far. More recently, Talaromyces cellulolyticus was also scored as a promising cellulases producer. In comparison to the Trichoderma and Aspergillus systems, Talaromyces enzymes have been less investigated. The present research dealt with the conversion of steam-pretreated corn stover by commercial blend of T. cellulolyticus enzymes with respect to the common blends. The paper also investigated the stability of the enzyme preparation and tested the use of additives (namely Tween 80, Tween 20, and BSA) to improve the enzymes performances and the hydrolysis efficiency. The results indicated that, at the same process conditions, T. cellulolyticus cellulases were more effective and yielded 20% more sugars compared to control blends. Furthermore, the cellulase components displayed a synergistic interaction with hemicellulases. The results indicate that cellulases from T. cellulolyticus are less affected by the high dry matter consistency and the use of additives could increase the total activity by around 50% and β-glucosidase capacity by 10-15%.


The divided visual world paradigm: eye tracking reveals hemispheric asymmetries in lexical ambiguity resolution.
Eye tracking was combined with the visual half-field procedure to examine hemispheric asymmetries in meaning selection and revision. In two experiments, gaze was monitored as participants searched a four-word array for a target that was semantically related to a lateralized ambiguous or unambiguous prime. Primes were preceded by a related or unrelated centrally-presented context word. In Experiment 1, unambiguous primes were paired with concordant weakly-related context words and strongly-related targets that were similar in associative strength to discordant subordinate-related context words and dominant-related targets in the ambiguous condition. Context words and targets were reversed in Experiment 2. A parallel study involved the measurement of event-related potentials (ERPs; Meyer, A. M., and Federmeier, K. D., 2007. The effects of context, meaning frequency, and associative strength on semantic selection: distinct contributions from each cerebral hemisphere. Brain Res. 1183, 91-108). Similar to the ERP findings, gaze revealed context effects for both visual fields/hemispheres when subordinate-related targets were presented: initial gaze revealed meaning activation when an unrelated context was utilized, whereas later gaze also revealed activation in the discordant context, indicating that meaning revision had occurred. However, eye tracking and ERP measures diverged when dominant-related targets were presented: for both visual fields/hemispheres, initial gaze indicated the presence of meaning activation in the discordant context, and, for the right hemisphere, discordant context information actually facilitated gaze relative to unrelated context information. These findings are discussed with respect to the activeness of the task and hemispheric asymmetries in the flexible use of context information.


Magnesium cation induced conformational change of yeast tRNAPhe as studied by singlet-singlet energy transfer.
The A76 or A73 nucleotide at the 3'end of tRNAPhe was modified with the fluorescent reagent of proflavine (PF). The distance between the fluorophore of the 3'end and the Y base was measured by singlet-singlet energy transfer under the conditions of 10 mM and 0.01 mM Mg2+. The distance obtained at 10 mM Mg2+ is very close to that obtained by the X-ray diffraction method, while the distance at 0.01 mM Mg2+ is significantly smaller. The difference in the distance is explained as a result of destabilization of the tertiary structure with reduction of the Mg2+ concentration. The calculated distance between A73 and A76 shows the stacked conformation of the CCA strand. Fluorescent quenching experiments showed that the degree of stabilization of 3'end A76 by stacking is lower than that of A73. The removal of the CCA segment causes a difference not only in the thermal melting curves but also in the fluorescent wavelength of the Y base at 0.01 mM Mg2+. The results suggest that the 3'end CCA strand has a helical structure and contributes to the stabilization of the whole structure of tRNAPhe.


Rational Engineering of a Designed Protein Cage for siRNA Delivery.
Oligonucleotide therapeutics have transformative potential in modern medicine but are poor drug candidates in themselves unless fitted with compensatory carrier systems. We describe a simple approach to transform a designed porous protein cage into a nucleic acid delivery vehicle. By introducing arginine mutations to the lumenal surface, a positively supercharged capsule is created, which can encapsidate oligonucleotides in vitro with high binding affinity. We demonstrate that the siRNA-loaded cage is taken up by mammalian cells and releases its cargo to induce RNAi and knockdown gene expression. These general concepts could also be applied to alternative scaffold designs, expediting the development of artificial protein cages toward delivery applications.


Female survival, lifetime reproductive success and mating status in a passerine bird.
In facultatively polygynous birds, secondary females of polygynously mated males typically have reduced annual reproductive success, because polygynous males provide less paternal care than monogamous males. Life history theory predicts that, as a result of increased reproductive investment, secondary females should suffer from reduced survival and lifetime reproductive success, but previous studies provided only weak support for this hypothesis. We used 7 years of data to study the fitness of female collared flycatchers Ficedula albicollis in relation to mating status by estimating survival and lifetime reproductive success. Taking differences in recapture probability into account, a mark-recapture analysis revealed that females observed at least once to breed as secondary female had higher survival than other females. This relationship was not confounded by laying date, because when we assessed the impact of laying date on survival, we found similar survival patterns. Females of polygynous males had reduced breeding success in terms of number of young fledged during the current reproductive event. However, during their lifetime females found at least once in primary or secondary mating status produced significantly more eggs, and at least the same number of fledglings and recruits as monogamous females. Thus, in the collared flycatcher, females of polygynously mated males seem to suffer from mating status during the most recent reproductive event, but considering survival and lifetime reproductive success, the apparently disadvantageous mating event is not necessarily associated with reduced residual reproductive value.


Contribution of job-exposure matrices for exposure assessment in occupational safety and health monitoring systems: application from the French national occupational disease surveillance and prevention network.
To detect new hazards ("signals"), occupational health monitoring systems mostly rest on the description of exposures in the jobs held and on reports by medical doctors; these are subject to declarative bias. Our study aims to assess whether job-exposure matrices (JEMs) could be useful tools for signal detection by improving exposure reporting. Using the French national occupational disease surveillance and prevention network (RNV3P) data from 2001 to 2011, we explored the associations between disease and exposure prevalence for 3 well-known pathology/exposure couples and for one debatable couple. We compared the associations measured when using physicians' reports or applying the JEMs, respectively, for these selected diseases and across non-selected RNV3P population or for cases with musculoskeletal disorders, used as two reference groups; the ratio of exposure prevalences according to the two sources of information were computed for each disease category. Our population contained 58,188 subjects referred with pathologies related to work. Mean age at diagnosis was 45.8 years (95% CI 45.7; 45.9), and 57.2% were men. For experts, exposure ratios increase with knowledge on exposure causality. As expected, JEMs retrieved more exposed cases than experts (exposure ratios between 12 and 194), except for the couple silica/silicosis, but not for the MSD control group (ratio between 0.2 and 0.8). JEMs enhanced the number of exposures possibly linked with some conditions, compared to experts' assessment, relative to the whole database or to a reference group; they are less likely to suffer from declarative bias than reports by occupational health professionals.


Synthesis and Characterization of Chitosan-Based Polyelectrolyte Complexes Doped with Xanthene Dyes.
Biocompatible chitosan-based polyelectrolyte complexes (PECs) doped with xanthene dyes (fluorescein, eosin Y, erythrosin B, rhodamine 6G) were synthesized and characterized by scanning electron microscopy, dynamic light scattering, zeta potential measurements, and absorption and luminescence (including polarized, time-resolved, and phosphorescence) spectroscopy. The results are discussed in terms of the mechanism and rigidity of dye-PEC binding, the heavy-atom effect in dyes and PEC stability. Eosin Y is found to be the optimal dopant, providing both a high dye content in PECs and a high quantum yield of fluorescence.


Dearomative cyclization of pyridines/isoquinolines with cyclopropenones: access to indolizinones and benzo-fused indolizinones.
Dearomatization reactions provide a rapid approach to construct complicated molecules that are difficult to synthesize by traditional methods from simple aromatic compounds. Herein, we report an efficient dearomative [3+2] cycloaddition reaction of 2-alkynyl pyridines with diarylcyclopropenones, leading to the synthesis of densely functionalized indolizinones in moderate to good yields under metal-free conditions. In addition, this strategy can also be employed in dearomative cyclization of isoquinolines to access a variety of benzo-fused indolizinones. Density functional theory (DFT) calculations revealed that an appropriate substituent at the 2-position of pyridine is crucial to the dearomatization process.


Effects of student participation in school health promotion: a systematic review.
The aim of this systematic review was to summarize systematically the existing evidence for the effects of student participation in designing, planning, implementing and/or evaluating school health promotion measures. The focus was on the effects of participation in school health promotion measures rather than on student involvement at school in general. Participation is a core value for health promotion but empirical evidence of its outcomes is scarce. We searched major bibliographic databases (including ASSIA, ERIC, PsycINFO, Scopus, PubMed and the Social Sciences Citation Index). Two reviewers independently decided about inclusion and exclusion of the identified abstracts (n = 5075) and full text articles. Of the 90 full text articles screened, 26 papers met the inclusion criteria. We identified evidence for positive effects, especially for the students themselves, the school as organization, and interactions and social relations at school. Almost all included studies showed personal effects on students referring to an increased satisfaction, motivation and ownership, an increase in skills, competencies and knowledge, personal development, health-related effects and influence on student perspective. Given that student participation has more been discussed as a value, or ideal of health promotion in schools, these findings documenting its effectiveness are important. However, further research is needed to consider the level or intensity of involvement, different approaches and stages of participation in the health promotion intervention, as well as mediating factors such as gender, socio-cultural background or academic achievement, in a more systematic manner.


Oral Medication Adherence Among Adolescents and Young Adults with Cancer Before and Following Use of a Smartphone-Based Medication Reminder App.
This study evaluated oral medication adherence among adolescents and young adults (AYAs) with cancer during a trial of a smartphone-based medication reminder application (app). Twenty-three AYAs receiving at least one prescribed, scheduled oral medication related to their outpatient cancer treatment participated in this 12-week single-group interrupted time series longitudinal design study. Baseline oral medication adherence was monitored using electronic monitoring caps for 4 weeks. Participants then used a medication reminder app and continued to have their oral medication adherence monitored for 8 weeks. Participants completed an electronically administered weekly survey addressing perceived adherence and reasons for nonadherence. Four adherence phenotypes were identified using visual graphical analysis of individual participants' weekly adherence: (1) high adherence during the preintervention and intervention periods (n = 13), (2) low preintervention adherence and improved adherence during the intervention period (n = 3), (3) low adherence during both periods (n = 6), and (4) high preintervention adherence and low adherence during the intervention period (n = 1). Growth curve models did not show significant changes in adherence by preintervention versus intervention trajectories (p > 0.05); however, the variance in adherence during the intervention narrowed for more highly adherent AYAs. "Forgetfulness" was the most frequently reported reason for nonadherence. Although overall adherence did not improve following use of the app, the variance decreased for more highly adherent participants. Additional or alternative interventions are needed for AYAs with persistently poor adherence. Assessment of adherence patterns may support individualized recommendation of tailored interventions.


The role of nailfold capillary dropout on mortality in systemic sclerosis.
Semi-quantitative wide-field nailfold capillaroscopy (NFC) is a simple technique with proven utility in the early diagnosis of systemic sclerosis (SSc). Its role in prognosis, however, remains uncertain. To investigate the possible utility of NFC in predicting survival. Patients with SSc listed on the South Australian Scleroderma Register (SASR) with prior NFC performed at Flinders Medical Centre from 1991 to 2015 were included in this study. Baseline demographic data, diagnosis, scleroderma antibody status and mortality status were also collected for each patient. The cohort consisted of 99 patients with limited cutaneous SSc, 30 patients with diffuse cutaneous SSc and 23 with an overlap scleroderma syndrome. Fifty-six patients died during the period of study (censured end June 2015). Patients with diffuse scleroderma had significantly greater capillary dropout compared with limited and overlap scleroderma (P < 0.001). In univariate analysis, both capillary dropout scores (log-rank χ2 = 8.75, P = 0.003) and antibody status (log-rank χ2 = 13.94, P = 0.003) were associated with mortality. ANOVA showed a significant association between antibody status and capillary dropout (P < 0.001). In Cox regression, adjustment for capillary dropout attenuated the impact of autoantibody group on survival. Nailfold capillary dropout was significantly associated with mortality and the severity of dropout attenuates survival dictated by antibody status. Together these observations support the hypothesis that capillary dropout is on the causal pathway between induction of scleroderma associated autoantibodies and mortality.


Periodic variation and its effect on management and prognosis of Korean patients with acute myocardial infarction.
The characteristics of the periodic variation in acute myocardial infarction (AMI) and the subsequent effect on management and prognosis have not been fully investigated in a large number of Asian populations. From a prospective, observational multicenter online registry, 4,573 patients diagnosed as AMI in Korea from January to December 2006 were included. The highest incidence of AMI was between 8 a.m. and noon. The number of cases was highest in the winter and lowest in the autumn (13.6 vs 11.4 patients per day, P<0.001). Patients with symptom onset during working hours had a shorter time to first medical contact (203+/-288 min) compared with out-of-hours onset (230+/-288 min, P=0.003). In patients who underwent primary angioplasty, out-of hours symptom onset was associated with a greater time delay in both the patient's and the medical facility's response (door-to-balloon time out-of hours vs working hours: 101+/-54 min vs 84+/-44 min, P<0.001). In patients with ST-segment elevation myocardial infarction, symptoms to first medical contact showed a significant relationship to in-hospital mortality (for every 10 min of symptoms to first medical contact, odds ratio 1.006, 95% confidence interval 1.001-1.012, P=0.018) Circadian and periodic variation in AMI exists in Korean patients, which resulted in different patient behavior, hospital management and outcomes.


The paradox of hypotension and pheochromocytoma: a case report.
Pheochromocytomas produce, store and secrete catecholamines. Diagnosis is often suspected in young patients with severe hypertension. We present the case of a 47-year-old woman without a previous history of hypertension, whose initial presentation was cardiovascular shock. Despite early diagnosis of the disease, the fulminant evolution of the pheochromocytoma crisis was fatal a few hours after admission. Only a few therapeutic options remain when haemodynamic collapse is catecholamine induced.


[Apoptosis of sperm induced by murine cytomegalovirus infection and its mechanism regulated by sperm mitochondria: experiment with mice].
To study the effects of murine cytomegalovirus (MCMV) infection on mature sperm apoptosis in mice, and to explore the mechanism of MCMV-induced apoptosis regulated by mitochondria. MCMV was inoculated into the testes of 15 BALB/c mice to establish acute MCMV infection models and 15 mice were used as controls. 1, 2, 4, 6, and 9 days after the infection 3 mice from each group were killed. Flow cytometry was used to observe the apoptosis of sperms. Laser scanning confocal microscopy was performed to examine the mitochondrial membrane potential (delta psi psi m) of sperm. The mitochondria ultrastructure of sperm was observed under electron microscope. The sperm apoptotic ratebeganto increase from day 2 after inoculation (D2 PI), peaked to the level of (39.3 +/- 1.0)% compared with that of the control group on D4 PI, and then fell-off (F = 362.822, P < 0.05). The delta psi m of sperm began to increase on D1 PI at the level of (74.0 +/- 1.4), began to decrease on D2 PI [( 63.0 +/- 2.2)], dropped to the minimum on D4 PI [(40.2 +/- 2.3)], then ascended slowly again (F = 32.257, P < 0.05). The mitochondria ultrastructure of sperm showed damage after MCMV infection that was especially severe from D2 PI to D6 PI. MCMV acute infection in reproductive organ induces apoptosis of mature sperm in the cauda epididymidis. Sperm mitochondria participate in and regulate initiatively the apoptosis of sperm.


Association between interleukin-4-producing T lymphocyte frequencies and reduced risk of graft-versus-host disease.
We have previously developed and used limiting dilution analysis to measure frequencies of alloreactive cytotoxic T cell precursors (CTLp) and interleukin (IL)-2-producing T helper cells (IL-2/HTLp) to assess the risk of graft-versus-host disease in bone marrow transplantation (BMT). However, no test has been available to measure precursor frequencies of the important IL-4-secreting subset. We have now established a limiting dilution analysis to measure the frequency of IL-4-producing T helper cells (IL-4/HTLp) using the IL-4-responsive indicator cell line CT.h4S and have applied this assay to measure alloreactive IL-4/HTLp frequencies in BMT donor-recipient pairs. These frequencies were then analyzed in the context of clinical data to assess the relationship between the number of donor anti-recipient IL-4-secreting T cells and disease outcome. Frequencies of IL-4/HTLp have been studied in HLA-identical siblings, HLA-"matched" unrelated, and HLA-mismatched combinations and found to range from approximately 1/500,000 in HLA-identical sibling pairs to -1/2,000 in HLA-DR-mismatched pairs. These frequencies were independent of those for IL-2/HTLp and showed a negative correlation with those for CTLp. Clinical follow-up of 30 patients showed that high IL-4/HTLp frequencies are associated with a reduced risk of severe graft-versus-host disease. High IL-4/HTLp frequencies may also indicate an increased risk of leukemia relapse. Our data suggest that measurement of IL-4/HTLp frequencies provides information distinct from that obtained with CTLp and IL-2/HTLp. This new assay provides a valuable additional method for optimizing donor selection in unrelated BMT.


Epidemiological, clinical and therapeutic features of pediatric kala-azar.
Kala-azar (visceral leishmaniasis) is endemic in southern Iran. We retrospectively evaluated 367 infants and children with visceral leishmaniasis at hospitals affiliated to Shiraz University of Medical Sciences in Fars Province (located in the southwestern part of Iran). Seasonal variation was observed with more cases presenting in late winter, spring and a few in summer. The predominant clinical features in these patients were chronic fever, pallor, weight loss, abdominal distention, and hepatosplenomegaly. Lymphadenopathy was less common. Common laboratory abnormalities included anemia, leukopenia, thrombocytopenia, hypoalbuminemia and hypergammaglobulinemia. Liver function tests were deranged in two-thirds of patients. Immuno-fluorescence antibody (IFA) test was positive in all patients and all had positive bone marrow smears or cultures for Leishmania donovani. Patients responded well to Glucantim therapy with a cure rate of 96.7%. Relapse was observed in 8.2%(30) of patients. Mortality in this series was 7.3%. Twenty-three patients died during therapy. Jaundice and grossly deranged liver function tests were bad prognostic signs.


Emotion recognition in patients with idiopathic Parkinson's disease.
Emotion recognition (ER) was examined in 64 patients with idiopathic Parkinson's disease (PD; 56 bilateral and 8 right-sided) and 64 matched healthy volunteers. Participants were administered an ER battery, consisting of the following subscores: overall ER (OER), overall facial ER, facial emotion identification (FEI) and discrimination, overall prosodic ER, and prosodic emotion identification (PEI) and discrimination. Measures of visuospatial functions, auditory attention, and depression were also administered. After controlling for visuospatial functions, auditory attention and depression, results indicated that patients with bilateral PD had poorer performance on all ER subscores, regardless of the modality and type of experimental task involved, relative to healthy volunteers. However, patients with right-sided PD had difficulty on FEI and PEI only. Whereas none of the clinical variables examined in this study predicted any of the ER subscores, visual organization and auditory attention positively predicted OER in patients with PD. In addition, visual organization also positively predicted FEI in these patients. Implications are discussed in terms of the neural substrates underlying ER.


Oxidized Hemoglobin Is Antigenic and Immunogenic in Lupus.
Hemolysis-associated anemia is characteristic of diseases such as atherosclerosis, lupus, malaria, and leishmaniasis; the toxic effects of free hemoglobin (Hb) have been extensively described. This study was based on the premise that release of this sequestered, inflammatory molecule can result in deleterious immunological consequences, particularly in the context of pre-existing lupus. IgG anti-Hb responses were detected in the sera of lupus patients. Lupus-prone mice exhibited heightened plasma Hb levels, and ferric (Fe3+) Hb triggered preferential release of lupus-associated cytokines from splenocytes derived from aging lupus-prone mice. Anti-Hb B cell precursor frequencies were heightened in such mice, which also expressed increased titers of anti-Hb antibodies in serum and in kidney eluates. Fe3+ Hb preferentially increased the functional maturation of bone marrow-derived dendritic cells (BMDCs) from lupus-prone mice, effects abrogated upon the inhibition of Stat3. Hb interacted with lupus-associated autoantigens extruded during apoptosis and coincubation of Hb and apoptotic blebs had additional maturation-inducing effects on lupus BMDCs. Immunization with Hb in lupus-prone mice induced antigen spreading to lupus-associated moieties; Hb-interacting autoantigens were preferentially targeted and increased complement deposition and glomerulosclerosis were observed. Hb therefore demonstrates both antigenicity and immunogenicity and triggers specific immuno-pathological effects in a lupus milieu.


Cluster scaling and critical points: A cautionary tale.
Many systems in nature are conjectured to exist at a critical point, including the brain and earthquake faults. The primary reason for this conjecture is that the distribution of clusters (avalanches of firing neurons in the brain or regions of slip in earthquake faults) can be described by a power law. Because there are other mechanisms such as 1/f noise that can produce power laws, other criteria that the cluster critical exponents must satisfy can be used to conclude whether or not the observed power-law behavior indicates an underlying critical point rather than an alternate mechanism. We show how a possible misinterpretation of the cluster scaling data can lead one to incorrectly conclude that the measured critical exponents do not satisfy these criteria. Examples of the possible misinterpretation of the data for one-dimensional random site percolation and the one-dimensional Ising model are presented. We stress that the interpretation of a power-law cluster distribution indicating the presence of a critical point is subtle and its misinterpretation might lead to the abandonment of a promising area of research.


Basal-Like Cell-Conditioned Medium Exerts Anti-Fibrotic Effects In Vitro and In Vivo.
In idiopathic pulmonary fibrosis (IPF), basal-like cells are atypically present in the alveolar region, where they may affect adjacent stromal cells by paracrine mechanisms. We here aimed to confirm the presence of basal-like cells in peripheral IPF lung tissue in vivo, to culture and characterize the cells in vitro, and to investigate their paracrine effects on IPF fibroblasts in vitro and in bleomycin-injured rats in vivo. Basal-like cells are mainly localized in areas of pathological bronchiolization or honeycomb cysts in peripheral IPF lung tissue. Single-cell RNA sequencing (scRNA-seq) demonstrated an overall homogeneity, the expression of the basal cell markers cytokeratin KRT5 and KRT17, and close transcriptomic similarities to basal cells in the majority of cells cultured in vitro. Basal-like cells secreted significant levels of prostaglandin E2 (PGE2), and their conditioned medium (CM) inhibited alpha-smooth muscle actin (α-SMA) and collagen 1A1 (Col1A1) and upregulated matrix metalloproteinase-1 (MMP-1) and hepatocyte growth factor (HGF) by IPF fibroblasts in vitro. The instillation of CM in bleomycin-injured rat lungs resulted in reduced collagen content, improved lung architecture, and reduced α-SMA-positive cells. Our data suggested that basal-like cells may limit aberrant fibroblast activation and differentiation in IPF through paracrine mechanisms.


Two-color pyrometry for low amplitude periodic heating.
Specimens subject to periodic heating must be probed for a calibrated temperature response if standard measurements of thermal diffusivity are to be extended to determine thermal conductivity. A variation on two-color pyrometry is developed to measure both the offset and harmonic amplitudes of temperature fluctuations caused by periodic heating. The requisite pyrometric formulae are derived for low amplitude heating using an expansion of the nonlinear thermal emission. Well-defined uncertainties in the temperature values are determined from experimental uncertainties in radiometric measurements. The accuracy demonstrated in this work is better than 2% for the temperature offset and 3%-8% for the fluctuating temperature amplitude.


Mobile Electronic Medical Records Promote Workflow: Physicians' Perspective From a Survey.
As a result of demographic changes, physicians are required to deliver needed services with limited resources. Research suggests that tablet PCs with access to patient data may streamline clinical workflow. A recent study found tablets with mobile electronic medical records (EMRs) can facilitate data retrieval and produce time savings across the clinical routine within hospital settings. However, the reasons for these time savings, including details on how tablets were being used, remain unclear. The same applies to physicians' perceptions of this tool within an inpatient setting. This study examined physicians' perception of tablets with EMRs in an inpatient setting. The rationale was to identify both subjective and objective factors that impacted the successful implementation and use of tablets running an EMR. We developed a 57-item survey questionnaire designed to examine users' perception of and attitude toward tablets, which was administered to 14 participating physicians following 7 weeks of tablet use. Five participants volunteered to participate in a second study that investigated physicians' patterns of tablet use within the EMR environment by digitally tracking and storing usage behavior. Statistical analyses of questionnaire results included mean values with their bootstrapped 95% confidence intervals and multivariate analysis of variance to identify predictors of tablet use. Physicians reported high degrees of satisfaction with the tablets. There was a general consensus among physicians that tablet use streamlined clinical workflow through optimized data retrieval (rated 0.69, 0.23-1.15 points better than control) and improved communication with patients and other physicians (rated 0.85, 0.54-1.15 and 0.77, 0.38-1.15 points better than control, respectively). Age (F3,11=3.54, P=.04), occupational group (F1,11=7.17, P=.04), and attitude toward novel technologies (F1,11=10.54, P=.02) predicted physicians' satisfaction with the devices and their motivation regarding their further use. Tracking data yielded that only a few of the available functions were used frequently. Although tablet PCs were consistently perceived as beneficial, several factors contributed to the fact that their full potential was not fully exploited. Training in functionality and providing a reliable infrastructure might foster successful tablet implementation.


Role for Lhx2 in corticogenesis through regulation of progenitor differentiation.
The neocortex represents the brain region that has undergone a major increase in its relative size during the course of mammalian evolution. The larger cortex results from a corresponding increase in progenitor cell number. The progenitors giving rise to neocortex are located in the ventricular zone of the dorsal telencephalon and highly express Lhx2, a LIM-homeodomain transcription factor. The neocortex fails to form in the Lhx2 constitutive knockout, indicating a role for Lhx2 in corticogenesis, but mid-embryonic lethality of the Lhx2 knockout requires the use of conditional strategies for further studies. Therefore, to explore Lhx2 function in neocortical progenitors, we generated mice with Lhx2 conditionally deleted from cortical progenitors at the onset of neurogenesis. We find that Lhx2 is critical for maintaining the proliferative state of neocortical progenitors during corticogenesis. In the conditional knockouts, the neocortex is formed but is significantly smaller than wild type. We find that deletion of Lhx2 leads to significantly decreased numbers of cortical progenitors and premature neuronal differentiation. A likely mechanism is indicated by our findings that Lhx2 is required for the expression of Hes1 in cortical progenitors, a key effector in the Notch signaling pathway that maintains the proliferative progenitor state. We conclude that Lhx2 regulates the balance between proliferation and differentiation in cortical progenitors and through this mechanism Lhx2 controls cortical size.


[Core of the philosophy of management: self-management].
Philosophy is an aspect of metaphysics; while management, by contrast is a practical matter. In this century, this is especially crucial that management philosophy focuses on value and spiritual intelligence. However, the core of pragmatic management is the manager's emotional intelligence. The purpose of this paper is to expound a manager's own positive values and philosophy, as well as the manager's capacity for the management of his or her own emotions. Ultimately, under a spiritually and emotionally intelligent manager, all aspects of an organization--personnel, business issues, physical assets--will interact harmoniously and the organization will advance.


Comparative study of the amount of backflow produced by four types of aortic valve prostheses.
To determine the extent of backflow encountered with currently used prosthetic valves, four types of aortic valves with comparable orifice diameters were tested in a pulse duplicating system. These were a Hancock porcine valve, a Lillehei-Kaster pivoting disk valve, a St. Jude bileaflet valve and a Björk-Shiley tilting disk valve. Mean aortic pressure was sequentially increased from 83 to 147 mmHg, keeping the pump rate essentially constant (69-73 strokes/min). The porcine valve produced the least amount of total backflow (backflow due to closure plus leakage backflow) (1.6 to 2.4 mL/stroke). Among the mechanical valves the Björk-Shiley valve showed the least amount of total backflow (5.0 to 6.0 mL/stroke). At a mean aortic pressure of 100 mmHg and a low cardiac output of 2 L/min, the total backflow with the porcine valve was only 6 percent of forward flow; whereas it was 19 percent with the Lillehei-Kaster valve, 22 percent with the St. Jude valve and 18 percent with the Björk-Shiley valve. Leakage backflow at a given level of mean aortic pressure was, as expected, directly related to the annular clearance area. It is concluded that the Hancock valve showed the least amount of backward flow, which would be particularly beneficial in low output states. In the presence of normal hemodynamics, the amount of backflow with the three mechanical valves appeared to be well below the level of backflow considered to be clinically significant.


SARS-CoV-2 neutralising antibody testing in Europe: towards harmonisation of neutralising antibody titres for better use of convalescent plasma and comparability of trial data.
We compared the performance of SARS-CoV-2 neutralising antibody testing between 12 European laboratories involved in convalescent plasma trials. Raw titres differed almost 100-fold differences between laboratories when blind-testing 15 plasma samples. Calibration of titres in relation to the reference reagent and standard curve obtained by testing a dilution series reduced the inter-laboratory variability ca 10-fold. The harmonisation of neutralising antibody quantification is a vital step towards determining the protective and therapeutic levels of neutralising antibodies.


Testosterone secretion and semen plasma enzyme activity in rams with genital pathology stimulated with GnRH.
Testosterone secretion in response to GnRH stimulation and enzymatic activity of semen plasma was evaluated comparatively in rams with or without genital abnormality. Scrota, testes and epididymides of 128 rams between 1.5 and 6 years old from various breeds were examined clinically and ultrasonographically. Bilaterally cryptorchid rams (n = 2), and rams with focal testicular degeneration (n = 3) or unilateral sperm granuloma localized in the caput (n = 3) epididymis or the cauda epididymis (n = 3), diagnosed by either clinical or ultrasonographic examination, were selected for the further investigation of spermatologic parameters, testosterone secretion in response to GnRH stimulation, and enzymatic activity of semen plasma before histopathologic confirmation of lesions. Except for the cryptorchid rams, sperm parameters determined in ejaculates were similar to intact controls (n = 3). GnRH administration increased plasma testosterone levels significantly irrespective of the type of genital pathology (P < 0.01). The testosterone response calculated based on area under the curve following GnRH administration in rams having genital abnormality was not significantly different from the controls. Aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activity in the semen plasma varied between rams, with the lowest mean values in the bilaterally cryptorchid group (P < 0.05). Spermatic granuloma localized either in the caput or cauda of the epididymis was associated with a significant reduction in the semen plasma AST activity compared to controls (P < 0.01). In conclusion, our results indicated that the ability of testicular tissue to secrete testosterone in response to GnRH stimulation in rams with bilateral cryptorchidism, focal testicular degeneration and unilateral sperm granuloma was similar to that of intact controls, and that reduced semen plasma AST activity may have a diagnostic value in the diagnosis of the epididymal obstruction in rams. Focal testicular degeneration did not influence AST, alkaline phosphatase (ALP) and LDH activity in semen plasma.


[Relation of postradiation superovulation to the development of embryos and progeny of Wistar rats].
In experiments with 470 primigravida Wistar rats and 2248 kid rats of the first generation a study was made of the relationship between the postirradiation superovulation and viability of embryos and offspring of females subjected to whole-body gamma-irradiation with doses of 1 to 4 Gy. The extent and durability of superovulation are a function of radiation dose while the superovulation itself is accompanied by an increased pre- or post-implantation death of embryos and a decreased postnatal survival of the offspring.


Obesity across the lifespan among persons with spina bifida.
Identify risk factors for obesity across the lifespan for individuals with spina bifida. Cross sectional chart review study of 203 patients aged 6-58 years. Obesity was based on body mass index. Rates were calculated for children aged 6-11 years; adolescents aged 12-19 years and adults aged > 20 years. Chi-square analyses were used to determine differences in obesity rates among subgroups. An ordered logistic regression model was developed for the three age groups to estimate the probability of a change in BMI classification from normal weight to overweight or overweight to obese, controlling for sex, functional motor level, shunt status and insurance status. Obesity rates for children, adolescents and adults were 18, 8 and 37%, respectively. Obesity rates were higher among adults (chi2 = 27, p < 0.01) and for individuals who were publicly insured (chi2 = 7.2, p < 0.03). The ordered regression model for children demonstrated no independent association between sex, shunt status, functional motor level or insurance status and change in BMI category. For adolescents, lower functional motor level (i.e. sacral) increased the risk of becoming obese (Odds Ratio: 2.13; 95% CI: 1.12-4.06; p < 0.02). Among adults, female sex increased risk (OR = 2.28; 95% CI: 1.03-5.04; p < 0.04). Obesity rates for children and adolescents with spina bifida are similar to the general population; however, obesity rates are higher among adults, particularly women. Risk factors are similar to those observed in the general population.


Optical Aggregation of Gold Nanoparticles for SERS Detection of Proteins and Toxins in Liquid Environment: Towards Ultrasensitive and Selective Detection.
Optical forces are used to aggregate plasmonic nanoparticles and create SERS-active hot spots in liquid. When biomolecules are added to the nanoparticles, high sensitivity SERS detection can be accomplished. Here, we pursue studies on Bovine Serum Albumin (BSA) detection, investigating the BSA-nanorod aggregations in a range from 100 µM to 50 nM by combining light scattering, plasmon resonance and SERS, and correlating the SERS signal with the concentration. Experimental data are fitted with a simple model describing the optical aggregation process. We show that BSA-nanorod complexes can be optically printed on non-functionalized glass surfaces, designing custom patterns stable with time. Furthermore, we demonstrate that this methodology can be used to detect catalase and hemoglobin, two Raman resonant biomolecules, at concentrations of 10 nM and 1 pM, respectively, i.e., well beyond the limit of detection of BSA. Finally, we show that nanorods functionalized with specific aptamers can be used to capture and detect Ochratoxin A, a fungal toxin found in food commodities and wine. This experiment represents the first step towards the addition of molecular specificity to this novel biosensor strategy.


Psychosocial environment for the integrated education opportunities of the disabled in Lithuania.
The policy of the diminution of the social isolation of the disabled is the main objective of the strategy of the EU new policy concerning the disabled. Lithuanian society faces this objective as well. For this reason, this study aiming at providing the theoretical basis for and predicting the possible psycho-social environment in an integrated education system, as well as at the evaluation of the reasons for the formation of a positive approach to the disabled, is especially relevant, since it creates the prerequisites for the optimisation of the process of the integration of disabled schoolchildren into the general system of education. The sample of the study consisted of 2471 children from the same schools: not integrated (1958), integrated (126) and special schools (382). Empirical methods: questionnaire poll, comparative analysis. The statistical analysis was carried out using SAS. Our study showed that the majority of schoolchildren without disabilities and disabled schoolchildren have positive intentions for interpersonal interactions (>82%) and positive emotions (>69%) independently of the discrepant character of interpersonal contacts, different conditions of education and family life, and despite of low level of knowledge. The results of the study confirmed positive intentions for interpersonal interaction between disabled schoolchildren and schoolchildren without disabilities, as well as a positive character of emotions, and disprove the unsound myth of the opponents of the social integration of the disabled stating that disabled children in comprehensive schools would undoubtedly experience offence from their peers without disabilities.


A human myeloma-produced monoclonal protein directed against the active subpopulation of von Willebrand factor.
The authors present a study of a human myeloma-produced monoclonal protein (IgG-k) directed against von Willebrand factor that caused an acquired von Willebrand's disease (vWD)-like syndrome. The illness was characterized by upper gastrointestinal bleeding, prolonged bleeding time, decreased platelet adhesiveness, lack of platelet aggregation in response to ristocetin, and a qualitatively abnormal Factor VIII related antigen (vWF) by two-dimensional immunoelectropheresis. Patient plasma or IgG fraction mixed with normal platelet-rich plasma completely inhibited aggregation with ristocetin, but patient platelets resuspended in normal plasma aggregated normally with ristocetin. VWF was markedly elevated and the two-dimensional immunoelectropheresis of vWF revealed a vWD type II-like pattern with an absence of the higher molecular weight forms of the vWF. Marked inhibitory activity was observed in the ristocetin cofactor assay but disappeared at the highest dilutions of patient plasma used in the assay. Infusion of cryoprecipitate following plasmapheresis led to a correction of the bleeding time, improvement in platelet adhesiveness, transient disappearance of inhibitory activity in the Factor VIII ristocetin cofactor assay, and no significant normalization of two-dimensional immunoelectropheresis of vWF. This case demonstrated a myeloma-associated monoclonal antibody that interacted specifically with that part of the Factor VIII molecule necessary for Factor VIII ristocetin cofactor activity, normal platelet adhesiveness, and bleeding time.


Management and Outcomes of Salmonella Gastroenteritis in the Era of Rapid Molecular Testing.
Molecular diagnostics provide a rapid and sensitive diagnosis of gastroenteritis compared with a stool culture. In this study, we seek to describe the changes in medical management and outcomes of children with Salmonella gastroenteritis as our hospital system adopted molecular diagnostics. This study is a retrospective chart review of children <18 years of age diagnosed with nontyphoidal Salmonella gastroenteritis between 2008 and 2018 at a large pediatric health care system in the southeastern United States. Those with immunocompromising conditions and hemoglobinopathies were excluded. Patients diagnosed via molecular testing were compared with those diagnosed solely by stool culture for aspects of management including admission rates, blood culture obtainment, and antibiotic administration. Of 965 eligible patients with Salmonella gastroenteritis, 264 (27%) had a stool molecular test and 701 (73%) only had a stool culture performed. Groups were similar in age and presentation. Those diagnosed by molecular methods had higher hospitalization rates (69% vs 50%, P <.001), more blood cultures obtained (54% vs 44%, P <.01), and received more antibiotics (49% vs 34%, P <.001) despite statistically similar rates of bacteremia (11% vs 19%, P = .05). The rapid diagnosis of Salmonella gastroenteritis by molecular methods was associated with increased hospital admission rates, blood culture obtainment, and antibiotic use. This suggests possible overmedicalization of uncomplicated Salmonella gastroenteritis, and clinicians should remain cognizant of the possibility of providing low-value care for uncomplicated disease.


Developing Optimized Treatment Plans for Patients with Dyslipidemia in the Era of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Therapeutics.
This educational content was derived from a live satellite symposium at the American College of Physicians Internal Medicine Meeting 2017 in San Diego, California (online at http://courses.elseviercme.com/acp/702e). This activity will focus on optimized treatment plans for patients with dyslipidemia in the era of proprotein convertase subtilisin/kexin type 9 inhibitor therapeutics. Low-density lipoprotein cholesterol has been identified as an important therapeutic target to prevent the progression of atherosclerotic disease; however, only 1 of every 3 adults with high low-density lipoprotein cholesterol has the condition under control. Expert faculty on this panel will discuss the science of proprotein convertase subtilisin/kexin type 9 inhibitors and aid physicians in the best practices to achieve low-density lipoprotein cholesterol target in their patients.


Stuck in a Moment: Tonic Immobility Predicts Poor Quality of Life in Treated PTSD Patients.
Posttraumatic stress disorder (PTSD) is a prevalent and disabling multisystem disorder, with significant physical and psychiatric morbidity and poor quality of life (QOL). Although peritraumatic reactions - tonic immobility and dissociation - are established predictors of PTSD severity and development, there is a dearth of investigation assessing the impact of peritraumatic reactions on QOL of PTSD patients. Quality of life has become increasingly important in health care and research as a reliable outcome measure. It comprises psychological, physical, social and environmental domains, providing important information about the impact of diseases on patient's life. This study aims to investigate the impact of peritraumatic tonic immobility and peritraumatic dissociation on QOL of PTSD civilian outpatients. It is a cross-sectional study of 50 victims of urban violence with current PTSD, recruited in a specialized outpatient clinic. Instruments used were: Structured Clinical Interview IV, Peritraumatic Dissociative Experiences Questionnaire, Tonic Immobility Scale and WHOQOL-BREF (psychological, physical, social and environmental domains). Linear regression models were fitted to evaluate the impact of peritraumatic reactions - tonic immobility and dissociation - on WHOQOL-BREF scores. We controlled for sex as potential confounding. The severity of peritraumatic tonic immobility negatively impacted on psychological and environment domains of quality of life. For each additional point on the Tonic Immobility Scale, there was a decreased of 0.8 points on the scores of these domains of WHOQOL-BREF. Neither the peritraumatic reactions showed effects on physical nor social domains. Possible limitations of this study include cross-sectional design, relatively small sample size of tertiary center outpatients and recall bias. Peritraumatic tonic immobility is related to poor quality of life, adding new insights about the relationship between this immobility reaction and PTSD.


Chlorine Incorporation for Enhanced Performance of Planar Perovskite Solar Cell Based on Lead Acetate Precursor.
We show the effects of chlorine incorporation in the crystallization process of perovskite film based on a lead acetate precursor. We demonstrate a fabrication process for fast grain growth with highly preferred {110} orientation upon only 5 min of annealing at 100 °C. By studying the correlation between precursor composition and morphology, the growth dynamic of perovskite film in the current system is discussed. In particular, we found that both lead acetate precursor and Cl incorporation are beneficial to perovskite growth. While lead acetate allows fast crystallization process, Cl improves perovskite crystallinity. Planar perovskite solar cells with optimized parameters deliver a best power conversion efficiency of 15.0% and average efficiency of 14.0% with remarkable reproducibility and good stability.


Risk calculation variability over time in ocular hypertensive subjects.
To investigate the longitudinal variability of glaucoma risk calculation in ocular hypertensive (OHT) subjects. We reviewed the charts of untreated OHT patients followed in a glaucoma referral practice for a minimum of 60 months. Clinical variables collected at baseline and during follow-up included age, central corneal thickness (CCT), intraocular pressure (IOP), vertical cup-to-disc ratio (VCDR), and visual field pattern standard deviation (VFPSD). These were used to calculate the 5-year risk of conversion to primary open-angle glaucoma (POAG) at each follow-up visit using the Ocular Hypertension Treatment Study and European Glaucoma Prevention Study calculator (http://ohts.wustl.edu/risk/calculator.html). We also calculated the risk of POAG conversion based on the fluctuation of measured variables over time assuming the worst case scenarios (final age, highest PSD, lowest CCT, highest IOP, and highest VCDR) and best case scenarios (baseline age, lowest PSD, highest CCT, lowest IOP, and lowest VCDR) for each patient. Risk probabilities (%) were plotted against follow-up time to generate slopes of risk change over time. We included 27 untreated OHT patients (54 eyes) followed for a mean of 98.3±18.5 months. Seven individuals (25.9%) converted to POAG during follow-up. The mean 5-year risk of conversion for all patients in the study group ranged from 2.9% to 52.3% during follow-up. The mean slope of risk change over time was 0.37±0.81% increase/y. The mean slope for patients who reached a POAG endpoint was significantly greater than for those who did not (1.3±0.78 vs. 0.042±0.52%/y, P<0.01). In each patient, the mean risk of POAG conversion increased almost 10-fold when comparing the best case scenario with the worst case scenario (5.0% vs. 45.7%, P<0.01). The estimated 5-year risk of conversion to POAG among untreated OHT patients varies significantly during follow-up, with a trend toward increasing over time. Within the same individual, the estimated risk can vary almost 10-fold based on the variability of IOP, CCT, VCDR, and VFPSD. Therefore, a single risk calculation measurement may not be sufficient for accurate risk assessment, informed decision-making by patients, and physician treatment recommendations.


Characterization of two cell lines with distinct phenotypes established from a patient with small cell lung cancer.
Two small cell lung cancer (SCLC) cell lines were established from pericardial and pleural effusions of a patient with histopathologically proven SCLC of the oat cell type. Chemotherapy was administered without response during the 148-day period prior to the establishment of the first cell line, SCLC-22H, and some of the same drugs were administered in the 15 days prior to the establishment of the second cell line, SCLC-21H. Both cell lines differed markedly in their biochemical, kinetic, and morphological properties. Although the biomarkers L-Dopa decarboxylase, bombesin, carcinoembryonic antigen, and neurotensin were detectable in SCLC-22H, they were undetectable or low in SCLC-21H. The population doubling time was twice as fast and the colony forming efficiency higher in SCLC-21H than in SCLC-22H. They both expressed high concentrations of the SCLC marker enzymes neuron-specific enolase and the creatine kinase isoenzyme BB and showed no significant differences in their chromosomal characteristics. c-myc was amplified and expressed in both cell lines, and SCLC-21H had an additional rearranged and amplified EcoRI c-myc fragment. Morphological differences were apparent in liquid culture, cytology, and xenograft histology; SCLC-21H grew much more loosely than SCLC-22H, and had more prominent nucleoli and more abundant cytoplasm. Ultrastructurally dense core granules were present in both cell lines. SCLC-21H thus expressed properties of the variant cell type of SCLC, whereas SCLC-22H had mixed classic/variant features. An in vivo progression of the patient's tumor from a pure small cell to a mixed small cell/large cell morphology could be demonstrated, which suggests that cell line SCLC-22H represents a cell type characteristic for the transitional phase of the tumor. The features of this cell line therefore define a new subclass of SCLC called transitional cell type. SCLC-22H may be of use to study the mechanisms involved in the classic to variant transition, which probably has a considerable impact on the prognosis and response to therapy.


A new quaternary thiophosphate, RbNb2(S2)3(PS4).
The structure of the new quaternary thiophosphate rubidium diniobium tris(disulfide) tetrathiophosphate, RbNb(2)(S2)(3)(PS4), is made up of one-dimensional (infinity)(1)[Nb(2)(S2)(3)(PS4)(-)] chains along the [101] direction, and these chains are separated from one another by Rb(+) ions. The chain is basically built up from [Nb(2)S(12)] units and tetrahedral [PS(4)] groups. The [Nb(2)S(12)] units are linked together to form a linear [Nb(2)S(9)] chain by sharing the S-S prism edge. Short and long Nb-Nb distances [2.888 (2) and 3.760 (2) A, respectively] alternate along the chain, and the anionic species S(2)(2-) and S(2-) are observed.


[Summary and prospect of early warning models and systems for infectious disease outbreaks].
This paper summarizes the basic principles and models of early warning for infectious disease outbreaks, introduces the early warning systems for infectious disease based on different data sources and their applications, and discusses the application potential of big data and their analysing techniques, which have been studied and used in the prevention and control of COVID-19 pandemic, including internet inquiry, social media, mobile positioning, in the early warning of infectious diseases in order to provide reference for the establishment of an intelligent early warning mechanism and platform for infectious diseases based on multi-source big data.


Sleep, sleepiness and yawning.
This chapter will discuss the relationship between yawning, sleep onset, awakening and sleepiness. Models concerning wake-sleep regulation will be discussed in relation to yawning. Yawning close to sleep, before and after, will be examined in several conditions and populations. Also, the time course of yawning and sleepiness assessed by subjective estimates will be described.


Artificial Intelligence Based Patient-Specific Preoperative Planning Algorithm for Total Knee Arthroplasty.
Previous studies have shown that the manufacturer's default preoperative plans for total knee arthroplasty with patient-specific guides require frequent, time-consuming changes by the surgeon. Currently, no research has been done on predicting preoperative plans for orthopedic surgery using machine learning. Therefore, this study aims to evaluate whether artificial intelligence (AI) driven planning tools can create surgeon and patient-specific preoperative plans that require fewer changes by the surgeon. A dataset of 5409 preoperative plans, including the manufacturer's default and the plans corrected by 39 surgeons, was collected. Features were extracted from the preoperative plans that describe the implant sizes, position, and orientation in a surgeon- and patient-specific manner. Based on these features, non-linear regression models were employed to predict the surgeon's corrected preoperative plan. The average number of corrections a surgeon has to make to the preoperative plan generated using AI was reduced by 39.7% compared to the manufacturer's default plan. The femoral and tibial implant size in the manufacturer's plan was correct in 68.4% and 73.1% of the cases, respectively, while the AI-based plan was correct in 82.2% and 85.0% of the cases, respectively, compared to the surgeon approved plan. Our method successfully demonstrated the use of machine learning to create preoperative plans in a surgeon- and patient-specific manner for total knee arthroplasty.


Non-Pediatric Nurses' Willingness to Provide Care to Pediatric Patients during a Disaster: An Assessment of Pediatric Surge Capacity in Four Midwestern Hospitals.
To assess non-pediatric nurses' willingness to provide care to pediatric patients during a mass casualty event (MCE). Nurses from 4 non-pediatric hospitals in a major metropolitan Midwestern region were surveyed in the fall of 2018. Participants were asked about their willingness to provide MCE pediatric care. Hierarchical logistical regression was used to describe factors associated with nurses' willingness to provide MCE pediatric care. In total, 313 nurses were approached and 289 completed a survey (response rate = 92%). A quarter (25.3%, n = 73) would be willing to provide MCE care to a child of any age; 12% (n = 35) would provide care only to newborns in the labor and delivery area, and 16.6% (n = 48) would only provide care to adults. Predictors of willingness to provide care to a patient of any age during an MCE included providing care to the youngest-age children during routine duties, reporting confidence in calculating doses and administering pediatric medications, working in the emergency department, being currently or previously certified in PALS, and having access to pediatric-sized equipment in the unit or hospital. Pediatric surge capacity is lacking among nurses. Increasing nurses' pediatric care self-efficacy could improve pediatric surge capacity and minimize morbidity and mortality during MCEs.


Pharmaceutical Intermediate-Modified Gold Nanoparticles: Against Multidrug-Resistant Bacteria and Wound-Healing Application via an Electrospun Scaffold.
Remedying a multidrug-resistant (MDR) bacteria wound infection is a major challenge due to the inability of conventional antibiotics to treat such infections against MDR bacteria. Thus, developing wound dressings for wound care, particularly against MDR bacteria, is in huge demand. Here, we present a strategy in designing wound dressings: we use a small molecule (6-aminopenicillanic acid, APA)-coated gold nanoparticles (AuNPs) to inhibit MDR bacteria. We dope the AuNPs into electrospun fibers of poly(ε-caprolactone) (PCL)/gelatin to yield materials that guard against wound infection by MDR bacteria. We systematically evaluate the bactericidal activity of the AuNPs and wound-healing capability via the electrospun scaffold. APA-modified AuNPs (Au_APA) exhibit remarkable antibacterial activity even when confronted with MDR bacteria. Meanwhile, Au_APA has outstanding biocompatibility. Moreover, an in vivo bacteria-infected wound-healing experiment indicates that it has a striking ability to remedy a MDR bacteria wound infection. This wound scaffold can assist the wound care for bacterial infections.


Sex differences in circadian food anticipatory activity are not altered by individual manipulations of sex hormones or sex chromosome copy number in mice.
Recent studies in mice have demonstrated a sexual dimorphism in circadian entrainment to scheduled feeding. On a time restricted diet, males tend to develop food anticipatory activity (FAA) sooner than females and with a higher amplitude of activity. The underlying cause of this sex difference remains unknown. One study suggests that sex hormones, both androgens and estrogens, modulate food anticipatory activity in mice. Here we present results suggesting that the sex difference in FAA is unrelated to gonadal sex hormones. While a sex difference between males and females in FAA on a timed, calorie restricted diet was observed there were no differences between intact and gonadectomized mice in the onset or magnitude of FAA. To test other sources of the sex difference in circadian entrainment to scheduled feeding, we used sex chromosome copy number mutants, but there was no difference in FAA when comparing XX, XY-, XY-;Sry Tg, and XX;Sry Tg mice, demonstrating that gene dosage of sex chromosomes does not mediate the sex difference in FAA. Next, we masculinized female mice by treating them with 17-beta estradiol during the neonatal period; yet again, we saw no difference in FAA between control and masculinized females. Finally, we observed that there was no longer a sex difference in FAA for older mice, suggesting that the sex difference in FAA is age-dependent. Thus, our study demonstrates that singular manipulations of gonadal hormones, sex chromosomes, or developmental patterning are not able to explain the difference in FAA between young male and female mice.


[Nodular regenerative hyperplasia as a complication of thiopurine treatment in a patient with inflammatory bowel disease].
Immunomodulator therapy with thiopurine analogues azathioprine or 6-mercaptopurine is commonly prescribed for the treatment of organ transplantation, inflammatory bowel disease, autoimmune diseases and malignancies. Hepatotoxicity due to thiopurine analogues usually presents as an increase in serum transaminase levels. Toxicity is usually not severe, and a dose reduction is effective in most patients. Nodular regenerative hyperplasia (NRH) is a very rare but potentially severe complication of thiopurine-containing therapy. NRH is often asymptomatic, neither biochemical nor molecular markers are indicative for NRH. The suspicion rises when there are clinical symptoms of portal hypertension or increases in transaminases levels orthrombocytopenia. Liver biopsy is essential for definitive diagnosis. This is a case report of a 40-year-old male patient with Crohn's disease who developed increased serum levels of liver enzymes and thrombocytopenia following the administration of thiopurine. Although treatment with thiopurine was discontinued, he has further progressed and presented with acute variceal bleeding due to portal hypertension. The diagnosis of nodular regenerative hyperplasia was proven by a liver biopsy. In conclusion, NRH is a very rare but potentially severe complication of thiopurine-containing immunosuppressive therapy for IBD.


Differential Trends in Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Infections in Four Health Care Facilities in a Single Metropolitan Area: A Retrospective Analysis.
Background: Prevalence of extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-E. coli) is increasing worldwide, but greatly varies geographically. We compared the prevalence of ESBL-E. coli infections at four distinct health care facilities in San Francisco, California. Methods: Antimicrobial susceptibility reports were obtained for E. coli isolates from (1) a county hospital, (2) a public skilled nursing facility, (3) a university hospital, and (4) a Veterans Affairs (VA) Medical Center. We compared change in frequency of ESBL-E. coli and antimicrobial resistance to trimethoprim-sulfamethoxazole between 2012 and 2018. Results: From 2012 to 2018, frequency of ESBL-E. coli increased in urine and nonurine isolates from the county hospital (urine: 1.1% per year, 95% confidence interval [CI]: 0.5-1.6, p < 0.01; nonurine: 1.9% per year, 95% CI: 0.9-2.9, p < 0.01) and in urine isolates from the VA hospital (0.9% per year, 95% CI: 0.3-1.4, p < 0.01). The frequency of trimethoprim-sulfamethoxazole resistance fluctuated in all facilities. Conclusions: At the skilled nursing facility, the prevalence of ESBL-E. coli was highest, but remained stable over time, while the prevalence of ESBL-E. coli increased among urine and nonurine isolates at the county hospital and urine isolates at the VA hospital. The temporal trend of ESBL-E. coli infections, even within one city, varied by health care facility.


Effects of antiplatelet agents on platelet-induced thrombin generation.
The influence of antiplatelet agents on platelet-induced thrombin generation may increase the risk of bleeding. Assessment of the endogenous thrombin potential (ETP), is therefore a parameter deserving attention in early pharmacodynamic studies with antiplatelet drugs. The aim ofthis study was to assess whether an automated ETP-assay can be used to determine possible inhibitory effects of antiplatelet drugs on platelet-associated thrombin generation. We first characterized the in vitro dose-response relationship of several platelet agonists (ADP, collagen, U46619, TRAP (amino acid sequence: SFLLRNP) and tissue factor (TF) using the generation of ETP. One submaximal concentration of each agonist was then used to assess the influence of in vivo treatment with aspirin (single oral dose of 500 mg as inhibitor of thromboxane synthesis) and clopidogrel (given orally for 6 days, as an inhibitor of the purinergic P2Y12-receptor on platelets) and in vitro treatment with abciximab (which inhibits the platelet glycoprotein IIb/IIIa-receptor for fibrinogen), on the ETP. The effect of TF and the other platelet inducers on thrombin generation was dose-dependent. Repeat measurements on samples from the same subject, with the same inducer concentration on 2 different occasions showed a variability of approx. 22% (absolute difference between 2 measurements as % of mean). The coefficient on variation of repeat measurements of one sample varied between 7% and 17%, depending on the inducer. After a single dose of aspirin, ETP was reduced by 25-40%, depending on the platelet activating agent used. The reduction in ETP with abciximab in vitro was more pronounced. In contrast, TF-induced ETP was not influenced by aspirin or abciximab. Clopidogrel, administered for 6 days, reduced the ETP by 60% when platelets were stimulated using 20 microM ADP, whereas collagen-induced ETP and TF-induced ETP remained unchanged. The ETP-method is a sensitive and reproducible method for the detection of drug effects on platelet-induced thrombin generation of high throughput, and can be recommended for studies on the pharmacodynamic profile of drugs interfering with platelet function.


Epilepsy priorities in Europe: A report of the ILAE-IBE Epilepsy Advocacy Europe Task Force.
The European Forum on Epilepsy Research (ERF2013), which took place in Dublin, Ireland, on May 26-29, 2013, was designed to appraise epilepsy research priorities in Europe through consultation with clinical and basic scientists as well as representatives of lay organizations and health care providers. The ultimate goal was to provide a platform to improve the lives of persons with epilepsy by influencing the political agenda of the EU. The Forum highlighted the epidemiologic, medical, and social importance of epilepsy in Europe, and addressed three separate but closely related concepts. First, possibilities were explored as to how the stigma and social burden associated with epilepsy could be reduced through targeted initiatives at EU national and regional levels. Second, ways to ensure optimal standards of care throughout Europe were specifically discussed. Finally, a need for further funding in epilepsy research within the European Horizon 2020 funding programme was communicated to politicians and policymakers participating to the forum. Research topics discussed specifically included (1) epilepsy in the developing brain; (2) novel targets for innovative diagnostics and treatment of epilepsy; (3) what is required for prevention and cure of epilepsy; and (4) epilepsy and comorbidities, with a special focus on aging and mental health. This report provides a summary of recommendations that emerged at ERF2013 about how to (1) strengthen epilepsy research, (2) reduce the treatment gap, and (3) reduce the burden and stigma associated with epilepsy. Half of the 6 million European citizens with epilepsy feel stigmatized and experience social exclusion, stressing the need for funding trans-European awareness campaigns and monitoring their impact on stigma, in line with the global commitment of the European Commission and with the recommendations made in the 2011 Written Declaration on Epilepsy. Epilepsy care has high rates of misdiagnosis and considerable variability in organization and quality across European countries, translating into huge societal cost (0.2% GDP) and stressing the need for cost-effective programs of harmonization and optimization of epilepsy care throughout Europe. There is currently no cure or prevention for epilepsy, and 30% of affected persons are not controlled by current treatments, stressing the need for pursuing research efforts in the field within Horizon 2020. Priorities should include (1) development of innovative biomarkers and therapeutic targets and strategies, from gene and cell-based therapies to technologically advanced surgical treatment; (2) addressing issues raised by pediatric and aging populations, as well as by specific etiologies and comorbidities such as traumatic brain injury (TBI) and cognitive dysfunction, toward more personalized medicine and prevention; and (3) translational studies and clinical trials built upon well-established European consortia.


What is it going to take to move youth-related HIV programme policies into practice in Africa?
HIV has been reported to be the leading cause of mortality amongst adolescents in Africa. This has brought attention to the changes in service provision and health management that many adolescents living with HIV experience when transferring from specialized paediatric- or adolescent-focused services to adult care. When transition is enacted poorly, adherence may be affected and the continuum of care disrupted. As the population of HIV-infected adolescents grows, effective and supported transition increases in significance as an operational imperative. Considerable gaps remain in moving policy to practice at global, national, and local levels. Policies that give clear definition to transition and provide standard operating procedures or tools to support this process are lacking. National guidelines tend to neglect transition. Beyond transition itself, there has been slow progress on the inclusion of adolescents in national policies and strategies. Guidance often overlooks the specific needs and rights of adolescents, in particular for those living with HIV. In some cases, prohibitive laws can impede adolescent access by applying age of consent restriction to HIV testing, counselling and treatment, as well as SRH services. Where adolescent-focused policies do exist, they have been slow to emerge as tangible operating procedures at health facility level. A key barrier is the nature of existing transition guidance, which tends to recommend an individualized, client-centred approach, driven by clinicians. In low- and middle-income settings, flexible responses are resource intensive and time consuming, and therefore challenging to implement amidst staff shortages and administrative challenges. First, national governments must adopt transition-specific policies to ensure that adolescents seamlessly receive appropriate and supportive care. Second, transition policies must form part of a broader adolescent-centred policy landscape and adolescent-friendly orientation and approach at health system level. Third, national actors must ensure that transition policies are supported at implementation level. Fourth, youth involvement and community mobilization are essential. Finally, further implementation research is urgently needed to better understand how to support young people and providers in achieving smooth transitions. Only by moving from policy to practice through supportive policies and their implementation will we be closer to including adolescents in the 2030 goal of ending AIDS.


Denervation supersensitivity of refractoriness in noninfarcted areas apical to transmural myocardial infarction.
Denervation supersensitivity was demonstrated in anesthetized dogs 5 to 10 days after transmural myocardial infarction produced by latex embolization of a diagonal branch of the left anterior descending coronary artery. Sympathetic efferent denervation in noninfarcted myocardium apical to the infarction was demonstrated by a 90% depletion of myocardial norepinephrine content in the apical (45 +/- 15 pg norepinephrine/g tissue) vs basal (437 +/- 76 pg/g tissue) regions and by the lack of effective refractory period (ERP) shortening during bilateral ansae subclaviae stimulation in 34% of sites apical to the infarction. Supersensitivity in the area apical to the infarction was manifested by an exaggerated shortening of the ERP during both norepinephrine and isoproterenol infusions, with an upward and leftward shift in the dose-response curves in the apical vs basal regions (p less than .001). The cellular mechanism for denervation supersensitivity did not involve detectable changes in the beta-adrenergic receptor adenylate cyclase system. There was no difference in the density of beta-adrenergic receptors ([125I]-cyanopindolol) in the apical (268.6 +/- 22.7 fmol/mg protein) vs the basal (253.5 +/- 24.8 fmol/mg protein) regions. Adenylate cyclase activity stimulated by guanosine triphosphate plus isoproterenol was slightly greater in the apical (58.7 +/- 17.4%) than in the basal (49.6 +/- 10.9%) region, but this difference did not reach statistical significance (p = .068). Muscarinic modulation of beta-receptor coupling (oxotremorine attenuation of guanosine triphosphate plus isoproterenol-stimulated adenylate cyclase activity) also was not significantly different at the apical (31.6 +/- 17.5% inhibition) and basal (21.4 +/- 20.9% inhibition) sites. These data show that a transmural myocardial infarction produces denervation supersensitivity in areas apical to the infarction, but in this preparation no differences in the total number or a redistribution of beta-adrenergic receptors or adenylate cyclase activity were detected.


Resource availability and adjustment of social behaviour influence patterns of inequality and productivity across societies.
Animal societies vary widely in the diversity of social behaviour and the distribution of reproductive shares among their group members. It has been shown that individual condition can lead to divergent social roles and that social specialisation can cause an exacerbation or a mitigation of the inequality among group members within a society. This work, however, has not investigated cases in which resource availability varies between different societies, a factor that is thought to explain variation in the level of cooperation and the disparities in reproductive shares within each social group. In this study, I focus on how resource availability mediates the expression of social behaviour and how this, in turn, mediates inequality both within and between groups. I find that when differences in resource availability between societies persist over time, resource-rich societies become more egalitarian. Because lower inequality improves the productivity of a society, the inequality between resource-rich and resource-poor societies rises. When resource availability fluctuates over time, resource-rich societies tend to become more unequal. Because inequality hinders the productivity of a society, the inequality between resource-rich and resource-poor societies falls. From the evolutionary standpoint, my results show that spatial and temporal variation in resource availability may exert a strong influence on the level of inequality both within and between societies.


[Observations of long-term treatment of arthrosis with naproxen].
In a previous open clinical trial with d-2-(6'-methoxy-2'-naphthyl)-propionic acid (naproxen) in 32 outpatients with osteoarthrosis, very good to good results were achieved in 6 patients, satisfactory in 12, fair in 5, and unsatisfactory in 9 patients. The severest side effect observed was a case of gastric bleeding in a female patient who had been previously treated with a drug containing phenylbutazone and prednisone. Since, furthermore, 6 out of 9 such patients who did not respond to therapy had to stop the durg prematurely because of minor side effects and since in another 6 there was a tendency to a reduction of the leucocyte count, we subsequently initiated a long-term efficacy and tolerance study in our department for chronic patients. This series comprised 15 patients, aged 66 to 86 years, with severe, partly immobilizing coxarthroses and gonarthroses. The length of treatment was 2 to 16 months (mean 10.5 months). During the first 3 months ESR determinations and complete blood counts were performed every two weeks, later at four-weekly intervals. The patients were questioned weekly as to the efficacy of the treatment and as to side effects. Neither changes of the laboratory data nor gastro-intestinal side effects were observed. In two patients -- one a female with multiple allergies -- treatment had to be stopped because of itching and exanthema, respectively. The analgesic effect of naproxen was evaluated as very good in 5 cases, good in 5, fair in 2, and unsatisfactory in 3 cases. In addition, we conducted another clinical trial in 15 outpatients with degenerative joint diseases (partly of the spinal column). Their age varied from 16 to 60 years. Naproxen was administered in daily doses from 500 to 750 mg for the duration of 6 to 12 weeks. In no case had treatment to be interrupted, nor was there any gastric intolerance or alteration of the blood count observed in this group. Clinical results were classified as satisfactory to good in 10 patients.


Beyond Cell Motility: The Expanding Roles of Chemokines and Their Receptors in Malignancy.
The anti-tumor activities of some members of the chemokine family are often overcome by the functions of many chemokines that are strongly and causatively linked with increased tumor progression. Being key leukocyte attractants, chemokines promote the presence of inflammatory pro-tumor myeloid cells and immune-suppressive cells in tumors and metastases. In parallel, chemokines elevate additional pro-cancerous processes that depend on cell motility: endothelial cell migration (angiogenesis), recruitment of mesenchymal stem cells (MSCs) and site-specific metastasis. However, the array of chemokine activities in cancer expands beyond such "typical" migration-related processes and includes chemokine-induced/mediated atypical functions that do not activate directly motility processes; these non-conventional chemokine functions provide the tumor cells with new sets of detrimental tools. Within this scope, this review article addresses the roles of chemokines and their receptors at atypical levels that are exerted on the cancer cell themselves: promoting tumor cell proliferation and survival; controlling tumor cell senescence; enriching tumors with cancer stem cells; inducing metastasis-related functions such as epithelial-to-mesenchymal transition (EMT) and elevated expression of matrix metalloproteinases (MMPs); and promoting resistance to chemotherapy and to endocrine therapy. The review also describes atypical effects of chemokines at the tumor microenvironment: their ability to up-regulate/stabilize the expression of inhibitory immune checkpoints and to reduce the efficacy of their blockade; to induce bone remodeling and elevate osteoclastogenesis/bone resorption; and to mediate tumor-stromal interactions that promote cancer progression. To illustrate this expanding array of atypical chemokine activities at the cancer setting, the review focuses on major metastasis-promoting inflammatory chemokines-including CXCL8 (IL-8), CCL2 (MCP-1), and CCL5 (RANTES)-and their receptors. In addition, non-conventional activities of CXCL12 which is a key regulator of tumor progression, and its CXCR4 receptor are described, alongside with the other CXCL12-binding receptor CXCR7 (RDC1). CXCR7, a member of the subgroup of atypical chemokine receptors (ACKRs) known also as ACKR3, opens the gate for discussion of atypical activities of additional ACKRs in cancer: ACKR1 (DARC, Duffy), ACKR2 (D6), and ACKR4 (CCRL1). The mechanisms involved in chemokine activities and the signals delivered by their receptors are described, and the clinical implications of these findings are discussed.


The role of glioma stem cells in glioma tumorigenesis.
Malignant gliomas, the most common type of primary brain tumor, account for 80% of malignant tumors in the central nervous system (CNS). There are three principal types of glioma: astrocytomas, oligodendrogliomas, and oligoastrocytomas. Glioma stem cells (GSCs) have been found in all types; however, many fundamental questions about GSCs remain unanswered. This review will examine the current state of knowledge regarding GSC origin and the signaling pathways implicated in GSC tumorigenesis. The outstanding challenges for the study of GSCs in the context of glioma progression will also be discussed.


The femininity of the analyst in professional practice.
The author puts forward the hypothesis that the wishes concerning genitality are present from the beginning, and especially the wish to make or to have a child. From this follows that pregenital sexual satisfactions would be mainly substitutes for genital satisfactions, which are not available because of the human fundamental prematurity. Woman's maternal aptitude enables her to fulfil, in displacing it, her dual incestuous wish, i.e. to keep her father's penis inside her during pregnancy, to recover the stage of merging with her mother by means of the fusion with the foetus. This would explain why women are less often murderers than men: an archaic matrix of the Oedipus complex would exist which aims at finding an access to the mother's belly, which means to make it perfectly smooth after getting rid of all its contents, that is of all obstacles. This need leads to a destruction of reality. The disposition to maternity is common to both sexes (through identification to the mother). The author wants to describe the disposition to maternity of the analyst in the treatment. The analytic situation would correspond to the triangle schema of the Oedipus complex: it favours the regression to the foetal stage, but, at the same time, the psychoanalytic framework constitutes a limit which cuts the child from the mother.


Statistical Analysis Plan for "An international multicenter study of isoelectric electroencephalography events in infants and young children during anesthesia for surgery".
This Statistical Analysis Plan details the statistical procedures to be applied for the analysis of data for the multicenter electroencephalography study. It consists of a basic description of the study in broad terms and separate sections that detail the methods of different aspects of the statistical analysis, summarized under the following headings (a) Background; (b) Definitions of protocol violations; (c) Definitions of objectives and other terms; (d) Variables for analyses; (e) Handling of missing data and study bias; (f) Statistical analysis of the primary and secondary study outcomes; (g) Reporting of study results; and (h) References. It serves as a template for researchers interested in writing a Statistical Analysis Plan.


The effects of chronic muscular activity on age-related changes in single fiber electromyography.
Single fiber electromyography ( SFEMG ) of the extensor digitorum communis (EDC) muscle and nerve conduction studies were performed on healthy, active elderly men (66-77 years old) to assess age-related changes in neuromuscular physiology and the effect of long-term increased muscular activity on these changes. The following two groups were studied: a control group and a group composed of men with occupationally greater usage of hand extensors. Fiber density and mean jitter were essentially the same in both groups; however, in the hand-user group there was greater variability in mean jitter and a significant increase in the prevalence of potential pairs with increased jitter or blocking. In both groups, slower nerve conduction velocities and lower amplitudes of sensory and motor evoked potentials tended to correlate with increased jitter and fiber density. These electrophysiological changes in healthy aged men are consistent with an extremely mild process of nerve terminal denervation and reinnervation. Although long-term increased synaptic activity did not greatly alter the rate or extent of this process, it did produce a higher incidence of abnormal potential pairs and greater variability in mean jitter.


Social intergration and change in activities of daily living in Japanese elderly.
The prospective association of social integration reported in 1987 with change in activities of daily living (ADL) over three years was examined in a cohort of 2200 Japanese elderly, aged 60 years and over. Social integration data was obtained from a national survey which measured both the quantity and frequency of attachment. Social ties were classified into five types: spouse, child(ren) living together, child(ren) living separately, friend, neighbor, and community group. Eight potential confounding variables--age, educational attainment, existence of chronic diseases, subjective well-being, drinking, sleeping hours, cigarette smoking, and exercise--were controlled using logistic regression analysis for each sex. Men who attended community group meetings more frequently had significantly less decline in ADL during the follow-up period for those who were ADL unimpaired at the baseline survey, and were also significantly more improved for those who were ADL impaired people at the baseline survey. Trends for women were not significant.


The Na⁺/H⁺ exchanger (NHE1) as a novel co-adjuvant target in paclitaxel therapy of triple-negative breast cancer cells.
Dysregulation of Na⁺/H⁺ exchanger isoform one (NHE1) activity is a hallmark of cells undergoing tumorigenesis and metastasis, the leading cause of patient mortality. The acidic tumor microenvironment is thought to facilitate the development of resistance to chemotherapy drugs and to promote extracellular matrix remodeling leading to metastasis. Here, we investigated NHE1 as a co-adjuvant target in paclitaxel chemotherapy of metastatic breast cancer. We generated a stable NHE1-knockout of the highly invasive, triple-negative, MDA-MB-231 breast cancer cells. The NHE1-knockout cells proliferated comparably to parental cells, but had markedly lower rates of migration and invasion in vitro. In vivo xenograft tumor growth in athymic nude mice was also dramatically decreased compared to parental MDA-MB-231 cells. Loss of NHE1 expression also increased the susceptibility of knockout cells to paclitaxel-mediated cell death. NHE1 inhibition, in combination with paclitaxel, resulted in a dramatic decrease in viability, and migratory and invasive potential of triple-negative breast cancer cells, but not in hormone receptor-positive, luminal MCF7 cells. Our data suggest that NHE1 is critical in triple-negative breast cancer metastasis, and its chemical inhibition boosts the efficacy of paclitaxel in vitro, highlighting NHE1 as a novel, potential co-adjuvant target in breast cancer chemotherapy.


[Growth inhibition of human hepatocellular carcinoma xenograft in nude mice by combined treatment with human cytokine-induced killer cells and chemotherapy].
To compare the inhibitory effects of cytokine-induced killer (CIK) cells alone, chemotherapeutic drug alone, and CIK cells combined with chemotherapeutic drug on the growth of hepatocellular carcinoma (HCC) cells transplanted in nude mice. Peripheral blood mononuclear cells (PBMC) collected from five healthy donors by blood cell separator were incubated in vitro to induce CIK cells in the presence of interferon-gamma (IFN-gamma), IL-2 and anti-CD3 monoclonal antibody (mAb). The phenotype of CIK cells was characterized by flow cytometric analysis. BEL-7402 HCC cells were inoculated subcutaneously to nude mice. On day 5, at the inoculation site were injected normal saline (group 1), CIK cells (3 x 10(7) and 6 x 10(7), group 2 and 3), mitomycin-C (MMC 80 microg in 0.2 ml, group 4), and CIK cells combined with MMC (group 5), respectively. The percentage of CD3(+), CD3(+)CD8(+), CD3(+)CD56(+), CD25(+) cells increased from 64.0%, 28.0%, 7.8%, and 9.1% to 94.7%, 67.7%, 61.3%, and 84.0% respectively after cytokine induction. The percentage of CD3(+) and CD3(+)CD8(+) cells remained at high levels during incubation period, but that of CD25(+) and CD3(+)CD56(+) cells peaked respectively on day 7 and 13 and then declined. During the 90-day observation, the tumor formation rates were 100%, 70.0%, 80.0%, 70.0% and 66.7%; and the mouse survival rates were 10.0%, 60.0%, 40.0%, 50.0% and 75.0%, respectively from group 1 to group 5. Compared to the other groups, in the combined therapy group of mice, not only the tumor grew slowly and but also showed more marked tissue necrosis. The growth inhibitory effect on human HCC transplanted in nude mice of combined CIK cells and MMC treatment is more potent than that of CIK cells or MMC alone.


Complement C1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice.
We explored the role of the classic complement pathway in atherogenesis by intercrossing C1q-deficient mice (C1qa-/-) with low-density lipoprotein receptor knockout mice (Ldlr-/-). Mice were fed a normal rodent diet until 22 weeks of age. Aortic root lesions were threefold larger in C1qa-/-/Ldlr-/- mice compared with Ldlr-/- mice (3.72 +/- 1.0% aortic root versus 1.1 +/- 0.4%; mean +/- SEM, P < 0.001). Furthermore, the cellular composition of lesions in C1qa-/-/Ldlr-/- was more complex, with an increase in vascular smooth muscle cells. The greater aortic root lesion size in C1qa-/-/Ldlr-/- mice occurred despite a significant reduction in C5b-9 deposition per lesion unit area, suggesting the critical importance of proximal pathway activity. Apoptotic cells were readily detectable by cleaved caspase-3 staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and electron microscopy in C1qa-/-/Ldlr-/-, whereas apoptotic cells were not detected in Ldlr-/- mice. This is the first direct demonstration of a role for the classic complement pathway in atherogenesis. The greater lesion size in C1qa-/-/Ldlr-/- mice is consistent with the emerging homeostatic role for C1q in the disposal of dying cells. This study suggests the importance of effective apoptotic cell removal for containing the size and complexity of early lesions in atherosclerosis.


Matrix solution fixation: histology-compatible tissue preparation for MALDI mass spectrometry imaging.
Mass spectrometry imaging (MSI) acquires a grid of spatially resolved mass spectra and provides a molecular landscape of a tissue. This can have a myriad of uses: from basic tissue characterization to a comprehensive pathological diagnosis. We have developed a fast, inexpensive, histology-compatible tissue preparation method for matrix-assisted laser desorption/ionization (MALDI)-MSI, which overcomes current sample preparation-imposed limitations in image resolution. Tissue sections are prepared via simultaneous fixation and matrix deposition. This is accomplished by incorporating the MALDI matrix into solvents that preserve tissue integrity when applied according to standard histology procedures. This concept was expanded to include multiple histology protocols, thereby enabling analysis to be tailored to a variety of biomolecules and tissue types.


De novo aortic insufficiency during long-term support on a left ventricular assist device: a systematic review and meta-analysis.
Aortic insufficiency (AI) may occur while supported on a left ventricular assist device (LVAD). We conducted a systematic review to determine the incidence, predictors, and consequences of AI during LVAD support. MEDLINE was searched for original studies presenting clinical data regarding patients who developed AI during LVAD implant. Seven observational studies (657 patients) were selected for review; 65% of patients underwent implantation with a continuous-flow device (Cf-LVAD). The incidence of AI was 25% (11-42%) (Support period: 412 ± 281 days). AI increased by 4% (1-6%) per month of support (p < 0.01). AI-positive patients were older at implant (weighted mean difference, 7.7 [4.3; 11.1]; p < 0.01). Female sex (0.002 ± 0.001; p = 0.01) and smaller body surface area (-0.003 ± 0.001 per m; p < 0.01) correlated with progressive AI. Destination therapy patients (odds ratio [OR], 5.3 [1.2, 24]; p = 0.02) and those with Cf-LVAD pumps were likely to develop AI (hazard ratio [HR], 2.2 [1.2, 3.8]; p < 0.01). A closed aortic valve was associated with AI (OR, 4.7 [1.9, 11.8]; p < 0.01). Survival was comparable in both cohorts (HR, 1.5 [0.81, 2.8]; p = 0.2). A significant number of patients develop de novo AI during LVAD support. Advanced age, longer support duration, continuous-flow pumps, and a closed aortic valve are associated with AI. Large cohort studies would improve our understanding of this condition.


[Smoking and pharmacological interactions].
Cigarette smoking can affect drug metabolism via pharmacokinetic and pharmacodynamic mechanisms, and a sudden change in smoking status can render patients at risk of serious adverse reactions, eg. after clozapine. Patients should be regularly monitored with regard to their smoking status and extent of cigarette consumption and doses of relevant medications adjusted accordingly.