Fetal diaphragmatic wounds heal with scar formation.
Fetal wound healing is fundamentally different from wound healing in the adult. Although experimental work in mice, rats, rabbits, monkeys, and sheep has demonstrated that fetal healing occurs without inflammation and scarring, all of these studies have been limited to fetal skin wounds. Whether all fetal tissues heal in a regenerative-like fashion is unknown. Amniotic fluid exposure may play an important role in scarless fetal skin wound healing, but the effect of amniotic fluid on fetal mesothelial wound healing has not been characterized. To investigate these questions we created bilateral linear diaphragmatic wounds in 100-day gestation fetal lambs (term = 145 days). The right thoracotomy was closed to exclude amniotic fluid. In contrast, the left thoracotomy was fashioned into an Eloesser flap which permitted the left diaphragmatic wound to be continually bathed in amniotic fluid. Wounds were harvested after 1, 2, 7, or 14 days and analyzed by light microscopy and immunohistochemistry with antibodies to collagen types I, III, IV, and VI. Whether bathed in or excluded from amniotic fluid, the mesothelial-lined diaphragm healed with scar formation and without evidence of muscle regeneration. Interestingly, diaphragmatic wounds exposed to amniotic fluid were covered by a thick fibrous collagen peel similar to that seen in gastroschisis bowel. These findings indicate that not all fetal tissues share the unique scarless healing properties of fetal skin.


Comparative effects of diltiazem and hydrochlorothiazide in blacks with systemic hypertension.
The blood pressure-lowering effects of a calcium-entry blocker, diltiazem (240 or 360 mg/day), and a thiazide diuretic, hydrochlorothiazide (50 or 100 mg/day), were studied in 20 black hypertensive patients. Supine blood pressure decreases of -34/-18 mm Hg for diltiazem and -29/-21 mm Hg for hydrochlorothiazide were noted after 14 weeks of therapy. Differences between drugs were not significant. Blood pressures were normalized in all 4 of the monotherapy nonresponders when the 2 drugs were combined. Significant adverse effects were not noted. These data suggest that diltiazem is an effective antihypertensive agent in black patients. As monotherapy, its blood pressure-lowering effect is equivalent to hydrochlorothiazide.


Zika virus causes placental pyroptosis and associated adverse fetal outcomes by activating GSDME.
Zika virus (ZIKV) can be transmitted from mother to fetus during pregnancy, causing adverse fetal outcomes. Several studies have indicated that ZIKV can damage the fetal brain directly; however, whether the ZIKV-induced maternal placental injury contributes to adverse fetal outcomes is sparsely defined. Here, we demonstrated that ZIKV causes the pyroptosis of placental cells by activating the executor gasdermin E (GSDME) in vitro and in vivo. Mechanistically, TNF-α release is induced upon the recognition of viral genomic RNA by RIG-I, followed by activation of caspase-8 and caspase-3 to ultimately escalate the GSDME cleavage. Further analyses revealed that the ablation of GSDME or treatment with TNF-α receptor antagonist in ZIKV-infected pregnant mice attenuates placental pyroptosis, which consequently confers protection against adverse fetal outcomes. In conclusion, our study unveils a novel mechanism of ZIKV-induced adverse fetal outcomes via causing placental cell pyroptosis, which provides new clues for developing therapies for ZIKV-associated diseases.


Secondary (iso)BAs cooperate with endogenous ligands to activate FXR under physiological and pathological conditions.
IsoBAs, stereoisomers of primary and secondary BAs, are found in feces and plasma of human individuals. BA signaling via the nuclear receptor FXR is crucial for regulation of hepatic and intestinal physiology/pathophysiology. Investigate the ability of BA-stereoisomers to bind and modulate FXR under physiological/pathological conditions. Expression-profiling, luciferase-assays, fluorescence-based coactivator-association assays, administration of (iso)-BAs to WT and cholestatic mice. Compared to CDCA/isoCDCA, administration of DCA/isoDCA, UDCA/isoUDCA only slightly increased mRNA expression of FXR target genes; the induction was more evident looking at pre-mRNAs. Notably, almost 50% of isoBAs were metabolized to 3-oxo-BAs within 4 h in cell-based assays, making it difficult to study their actions. FRET-based real-time monitoring of FXR activity revealed that isoCDCA>CDCA stimulated FXR, and isoDCA and isoUDCA allowed fully activated FXR to be re-stimulated by a second dose of GW4064. In vivo co-administration of a single dose of isoBAs followed by GW4064 cooperatively activated FXR, as did feeding of UDCA in a background of endogenous FXR ligands. However, in animals with biliary obstruction and concomitant loss of intestinal BAs, UDCA was unable to increase intestinal Fgf15. In contrast, mice with an impaired enterohepatic circulation of BAs (Asbt-/-, Ostα-/-), administration of UDCA was still able to induce ileal Fgf15 and repress hepatic BA-synthesis, arguing that UDCA is only effective in the presence of endogenous FXR ligands. Secondary (iso)BAs cooperatively activate FXR in the presence of endogenous BAs, which is important to consider in diseases linked to disturbances in BA enterohepatic cycling.


The effect of (-)-hydroxycitrate on energy intake and satiety in overweight humans.
Assessment of the effects of 2 weeks of daily administration of HCA on energy intake and satiety in overweight men and women. A 6-week randomized placebo-controlled single-blinded cross-over trial. consumed three times daily for 2 weeks 100 ml tomato juice (placebo) and, separated by a 2 week wash-out period, 100 ml tomato juice with 300 mg HCA.Subjects: Twelve males and 12 females (body mass index 27.5+/-2.0 kg/m(2); age 37+/-10 y). After 2 weeks, 24 h energy intake (EI), appetite profile, hedonics, mood and possible change in dietary restraint were assessed in the laboratory restaurant. Prevention of degradation and bio-availability was documented. Twenty-four-hour EI was decreased by 15-30% (P<0.05) with HCA treatment compared to placebo, without changes in the appetite profile, dietary restraint, mood, taste perception and hedonics, while body weight tended to decrease (P=0.1). HCA treatment reduced 24 h EI in humans while satiety was sustained.


Ultrastructural localization of three major basement membrane components--type IV collagen, heparan sulfate proteoglycan and laminin in the normal human GBM.
Human glomerular basement membrane (GBM) is known to contain type IV collagen, heparan sulfate proteoglycan (HS-PG) and laminin in the extracellular matrix. In this study, ultrastructural distribution of these antigens was investigated in normal human glomeruli using the immunogold technique. Type IV collagen was present throughout the GBM, mainly on the lamina densa, and all over the mesangial region. HS-PG was present on the laminae rarae, predominantly on the lamina rara externa, and periphery of the mesangial region. Laminin was present throughout the GBM and peripheral region of the mesangial matrix. Our study demonstrated the preferential localization of each component in the GBM.


Validity of stroke severity assessment using medical records in a population-based cohort.
Stroke severity is an important prognostic indicator of morbidity and mortality, but often not recorded outside of specialised stroke centres. We aimed to develop a scoring rule and validate standardised assessment of the National Institutes of Health Stroke Scale (NIHSS) from medical records. We developed a standardised assessment of the NIHSS from medical records. Four trained raters independently assessed the charts of 100 patients with first-ever stroke, randomly selected from the population-based Rotterdam Study cohort. Interrater agreement was determined using the intraclass correlation coefficient (ICC), and Fleiss' kappa for major versus minor stroke. We validated the scoring method against 29 prospective, clinical NIHSS ratings, using Kendall's tau and Cohen's kappa. Of 100 included patients with stroke (mean age 80 years, 62% women), 71 (71%) were admitted to hospital and 9 (9%) were seen in outpatient clinic, whereas 20 (20%) were treated exclusively by their general practitioner or nursing home physician. Interrater agreement for retrospective, chart-based NIHSS ratings was excellent when assessed continuously (ICC: 0.90), and for minor versus major stroke (for NIHSS>3: κ=0.79, NIHSS>5: κ=0.78). Interrater agreement was good both for hospital-based and out-of-hospital settings (ICC: 0.97 and 0.75 respectively). Overall, assessment from medical records was in excellent agreement with prospective NIHSS ratings (τ=0.83; NIHSS>3: κ=0.93, and NIHSS>5: κ=0.93). However, for severe stroke (NIHSS>10) retrospective assessment tended to underestimate severity by 1-3 points on the NIHSS, which was accompanied by a somewhat lower interrater agreement for those more severe cases (NIHSS>10: κ=0.62). Assessment of stroke severity according to the NIHSS on the basis of medical records is feasible and reliable in population-based cohorts of patients with stroke. These findings facilitate more individualised risk estimates in observational studies that lack prospective ascertainment of stroke severity.


Symmetry groups of two-way twofold and three-way threefold fabrics.
This work discusses the symmetry groups of two classes of woven fabrics, two-way twofold fabrics and three-way threefold fabrics. A method to arrive at a design of a fabric is presented, employing methods in color symmetry theory. Geometric representations of all possible layer group or diperiodic symmetry structures of the fabrics are derived. There are 50 layer symmetry groups corresponding to two-way twofold fabrics and 27 layer symmetry groups corresponding to three-way threefold fabrics.


Colonography by computed tomography.
Computed tomographic colonography ('virtual colonoscopy') has shown promising results in the detection of large (> or = 10 mm) polyps in populations with a high prevalence of polyps. Recent studies in low prevalence populations, however, show variable results in sensitivity, ranging from 55% to 94% for the detection of patients with polyps measuring 10 mm or longer. Therefore questions have been raised about computed tomographic colonography as a screening method, probably the most valuable use of this technique. This article describes possible causes of these remarkable differences as well as advances in computed tomographic colonography.


Clinical characteristics and outcomes of a patient population with atypical hemolytic uremic syndrome and malignant hypertension: analysis from the Global aHUS registry.
Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) often caused by alternative complement dysregulation. Patients with aHUS can present with malignant hypertension (MHT), which may also cause TMA. This analysis of the Global aHUS Registry (NCT01522183) assessed demographics and clinical characteristics in eculizumab-treated and not-treated patients with aHUS, with (n = 71) and without (n = 1026) malignant hypertension, to further elucidate the potential relationship between aHUS and malignant hypertension. While demographics were similar, patients with aHUS + malignant hypertension had an increased need for renal replacement therapy, including kidney transplantation (47% vs 32%), and more pathogenic variants/anti-complement factor H antibodies (56% vs 37%) than those without malignant hypertension. Not-treated patients with malignant hypertension had the highest incidence of variants/antibodies (65%) and a greater need for kidney transplantation than treated patients with malignant hypertension (65% vs none). In a multivariate analysis, the risk of end-stage kidney disease or death was similar between not-treated patients irrespective of malignant hypertension and was significantly reduced in treated vs not-treated patients with aHUS + malignant hypertension (adjusted HR (95% CI), 0.11 [0.01-0.87], P = 0.036). These results confirm the high severity and poor prognosis of untreated aHUS and suggest that eculizumab is effective in patients with aHUS ± malignant hypertension. Furthermore, these data highlight the importance of accurate, timely diagnosis and treatment in these populations and support consideration of aHUS in patients with malignant hypertension and TMA. Atypical Hemolytic-Uremic Syndrome (aHUS) Registry. Registry number: NCT01522183 (first listed 31st January, 2012; start date 30th April, 2012).


Selecting relevant moderators with Bayesian regularized meta-regression.
When meta-analyzing heterogeneous bodies of literature, meta-regression can be used to account for potentially relevant between-studies differences. A key challenge is that the number of candidate moderators is often high relative to the number of studies. This introduces risks of overfitting, spurious results, and model non-convergence. To overcome these challenges, we introduce Bayesian Regularized Meta-Analysis (BRMA), which selects relevant moderators from a larger set of candidates by shrinking small regression coefficients towards zero with regularizing (LASSO or horseshoe) priors. This method is suitable when there are many potential moderators, but it is not known beforehand which of them are relevant. A simulation study compared BRMA against state-of-the-art random effects meta-regression using restricted maximum likelihood (RMA). Results indicated that BRMA outperformed RMA on three metrics: BRMA had superior predictive performance, which means that the results generalized better; BRMA was better at rejecting irrelevant moderators, and worse at detecting true effects of relevant moderators, while the overall proportion of Type I and Type II errors was equivalent to RMA. BRMA regression coefficients were slightly biased towards zero (by design), but its residual heterogeneity estimates were less biased than those of RMA. BRMA performed well with as few as 20 studies, suggesting its suitability as a small sample solution. We present free open source software implementations in the R-package pema (for penalized meta-analysis) and in the stand-alone statistical program JASP. An applied example demonstrates the use of the R-package.


Nerve Dependence: From Regeneration to Cancer.
Nerve dependence has long been described in animal regeneration, where the outgrowth of axons is necessary to the reconstitution of lost body parts and tissue remodeling in various species. Recent discoveries have demonstrated that denervation can suppress tumor growth and metastasis, pointing to nerve dependence in cancer. Regeneration and cancer share similarities in regard to the stimulatory role of nerves, and there are indications that the stem cell compartment is a preferred target of innervation. Thus, the neurobiology of cancer is an emerging discipline that opens new perspectives in oncology.


Metavalent Bonding in Layered Phase-Change Memory Materials.
Metavalent bonding (MVB) is characterized by the competition between electron delocalization as in metallic bonding and electron localization as in covalent or ionic bonding, serving as an essential ingredient in phase-change materials for advanced memory applications. The crystalline phase-change materials exhibits MVB, which stems from the highly aligned p orbitals and results in large dielectric constants. Breaking the alignment of these chemical bonds leads to a drastic reduction in dielectric constants. In this work, it is clarified how MVB develops across the so-called van der Waals-like gaps in layered Sb2 Te3 and Ge-Sb-Te alloys, where coupling of p orbitals is significantly reduced. A type of extended defect involving such gaps in thin films of trigonal Sb2 Te3 is identified by atomic imaging experiments and ab initio simulations. It is shown that this defect has an impact on the structural and optical properties, which is consistent with the presence of non-negligible electron sharing in the gaps. Furthermore, the degree of MVB across the gaps is tailored by applying uniaxial strain, which results in a large variation of dielectric function and reflectivity in the trigonal phase. At last, design strategies are provided for applications utilizing the trigonal phase.


Synthesis and crystal structure of tert-butyl 1-(2-iodo-benzo-yl)cyclo-pent-3-ene-1-carboxyl-ate.
1-(2-Iodo-benzo-yl)-cyclo-pent-3-ene-1-carboxyl-ates are novel substrates to construct bi-cyclo-[3.2.1]octa-nes with anti-bacterial and anti-thrombotic activities. In this context, tert-butyl 1-(2-iodo-benzo-yl)-cyclo-pent-3-ene-1-carboxyl-ate, C17H19IO3, was synthesized and structurally characterized. The 2-iodo-benzoyl group is attached to the tertiary C atom of the cyclo-pent-3-ene ring. The dihedral angle between the benzene ring and the mean plane of the envelope-type cyclo-pent-3-ene ring is 26.0 (3)°. In the crystal, pairs of C-H⋯O hydrogen bonds link the mol-ecules to form inversion dimers.


Improved mass spectrometric identification of gel-separated hydrophobic membrane proteins after sodium dodecyl sulfate removal by ion-pair extraction.
Separation and identification of hydrophobic membrane proteins is a major challenge in proteomics. Identification of such sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)-separated proteins by peptide mass fingerprinting (PMF) via matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) is frequently hampered by the insufficient amount of peptides being generated and their low signal intensity. Using the seven helical transmembrane-spanning proton pump bacteriorhodopsin as model protein, we demonstrate here that SDS removal from hydrophobic proteins by ion-pair extraction prior to in-gel tryptic proteolysis leads to a tenfold higher sensitivity in mass spectrometric identification via PMF, with respect to initial protein load on SDS-PAGE. Furthermore, parallel sequencing of the generated peptides by electrospray ionization-mass spectrometry (ESI-MS) and tandem mass spectrometry (MS/MS) was possible without further sample cleanup. We also show identification of other membrane proteins by this protocol, as proof of general applicability.


Reimbursement for reconstruction by tissue transfer-a European comparison.
Case payment mechanisms have become the principal means of remunerating hospitals in most developed countries. Our purpose was to analyse the reimbursement for different types of tissue transfer in five European countries. We looked at common surgical options for pedicled and free flaps. The recipient site of a flap and the principal diagnosis were systematically modified and processed with national grouper software in order to identify Diagnosis-Related Groups from which the proceeds were derived. The primary data originated from the database of the German Institute for the Hospital Remuneration System as aggregate information. We conducted eight specialist interviews to transfer the available data into clinical practice. Data of real patients were not available and we rather simulated standard patients to avoid dilution of results. Altogether, payment for pedicled flaps averaged 5933€ and was 8517€ for free flaps. The comparison of both flap types within a country revealed significant differences in Germany, Austria and Sweden only (p < 0.001). Italy has the highest mean proceeds for pedicled flaps, followed by Sweden, Germany, Austria and the UK. This relationship changes for free flaps with Sweden achieving the highest payments. Overall, reimbursement conformity is higher for free flaps. Most countries have procedure-driven payment systems for flap surgery, which additionally can strongly depend on the diagnosis. Nevertheless the latter does not always justify existing price differences. For the first time, clinical cases in tissue transfer were compared internationally. In today`s dynamic world of health care, we should observe other countries` compensation systems to identify ways of improving our own.


Glutamatergic synaptic dysregulation in schizophrenia: therapeutic implications.
Schizophrenia affects approximately 1% of the population and continues to be associated with poor outcome because of the limited efficacy of and noncompliance with existing antipsychotic medications. An alternative hypothesis invoking the excitatory neurotransmitter, glutamate, arose out of clinical observations that NMDA receptor antagonists, the dissociative anesthetics like ketamine, can replicate in normal individuals the full range of symptoms of schizophrenia including psychosis, negative symptoms, and cognitive impairments. Low dose ketamine can also re-create a number of physiologic abnormalities characteristic of schizophrenia. Postmortem studies have revealed abnormalities in endogenous modulators of NMDA receptors in schizophrenia as well as components of a postsynaptic density where NMDA receptors are localized. Gene association studies have revealed several genes that affect NMDA receptor function whose allelic variants are associated with increased risk for schizophrenia including genes encoding D-amino acid oxidase, its modulator G72, dysbindin, and neuregulin. The parvalbumin-positive, fast-firing GABAergic interneurons that provide recurrent inhibition to cortical-limbic pyramidal neurons seem to be most sensitive to NMDA receptor hypofunction. As a consequence, disinhibition of glutamatergic efferents disrupts cortical processing, causing cognitive impairments and negative symptoms, and drives subcortical dopamine release, resulting in psychosis. Drugs designed to correct the cortical-limbic dysregulated glutamatergic neurotransmission show promise for reducing negative and cognitive symptoms of schizophrenia as well as its positive symptoms.


Spatial deficits and hemispheric asymmetries in the rat following unilateral and bilateral lesions of posterior parietal or medial agranular cortex.
Studies of spatial behavior in both the human and non-human primate have generally focused on the role of the posterior parietal and prefrontal cortices and have indicated that destruction of these regions produce allocentric and egocentric deficits, respectively. The present study examined the role of the rodent analogs of these regions, the posterior parietal (PPC) and medial agranular (AGm) cortices, in egocentric and allocentric spatial processing, and whether spatial processing in rodents is organized in a hemispatial and/or lateralized manner as has been found in the primate. Eighty male rats receiving either a unilateral or bilateral lesion of AGm or PPC were examined on an egocentric (adjacent arm) or an allocentric (cheeseboard) maze task. The results indicated that PPC and AGm have dissociable spatial functions. Bilateral AGm destruction resulted in egocentric spatial deficits, and unilateral AGm operates demonstrated an intermediate deficit. In contrast, bilateral PPC operates demonstrated a severe deficit in allocentric processing. In addition, there were lateralized differences in the performance of unilateral PPC operates. While right PPC lesions resulted in a significant deficit on the allocentric task, no such deficit was seen in left PPC operates. In addition, neither unilateral AGm nor unilateral PPC operates demonstrated a hemispatial impairment on either the egocentric or allocentric tasks.


Auditory cues facilitate object movement processing in human extrastriate visual cortex during simulated self-motion: A pilot study.
Visual segregation of moving objects is a considerable computational challenge when the observer moves through space. Recent psychophysical studies suggest that directionally congruent, moving auditory cues can substantially improve parsing object motion in such settings, but the exact brain mechanisms and visual processing stages that mediate these effects are still incompletely known. Here, we utilized multivariate pattern analyses (MVPA) of MRI-informed magnetoencephalography (MEG) source estimates to examine how crossmodal auditory cues facilitate motion detection during the observer's self-motion. During MEG recordings, participants identified a target object that moved either forward or backward within a visual scene that included nine identically textured objects simulating forward observer translation. Auditory motion cues 1) improved the behavioral accuracy of target localization, 2) significantly modulated the MEG source activity in the areas V2 and human middle temporal complex (hMT+), and 3) increased the accuracy at which the target movement direction could be decoded from hMT+ activity using MVPA. The increase of decoding accuracy by auditory cues in hMT+ was significant also when superior temporal activations in or near auditory cortices were regressed out from the hMT+ source activity to control for source estimation biases caused by point spread. Taken together, these results suggest that parsing object motion from self-motion-induced optic flow in the human extrastriate visual cortex can be facilitated by crossmodal influences from auditory system.


The Therapeutic Effect and Potential Pharmacological Mechanisms of Ding-Zhi-Xiao-Wan on Depression were Investigated by Meta-analysis, Network Pharmacology and Molecular Docking.
Ding-Zhi-Xiao-Wan (DZXW) produces potential antidepressant-like effects. However, its antidepressant mechanisms are still unclear. To analyze the antidepressant effects and the pharmacological mechanisms of DZXW, meta-analysis, network pharmacology, and molecular docking were selected in this study. The compounds of DZXW and genes associated with compounds or depression were obtained from databases. The genes overlapping between DZXW compounds and depression were compared by Venn diagram. A network of medicine-ingredients-targets-disease was constructed, visualized, and analyzed. Protein-protein interaction, gene ontology, pathway enrichment, and molecular docking were performed to evaluate the potential mechanisms of DZXW for the treatment of depression. Meta-analysis showed that the antidepressant-like effects were produced by DZXW. The network pharmacology analysis showed that a total of 74 compound-related genes and 12607 PTSD-related genes were identified in the databases with 65 overlapping genes. The active ingredients derived from DZXW (i.e Beta-sitosterol, Stigmasterol, Fumarine, Hederagenin) elicited the antidepressant-like effects by targets, such as ACHE, HTR2A, and CHRM1. Moreover, the signaling pathways, like neuroactive ligand-receptor interaction, pathways in cancer, and cholinergic synapse, might play important roles in the treatment of depression by DZXW. This study provides studies analysis and molecular evidence with the beneficial effects of DZXW for the treatment of depression.


Greater early weight gain and shorter breastfeeding are associated with low adolescent adiponectin levels.
Early life factors can programme future risk for cardiovascular disease. We explored associations between adolescent adiponectin levels and concomitant metabolic alteration and also looked at the association between early life factors and adolescent adiponectin levels. We studied a longitudinal cohort of low-income to middle-income Chilean adolescents who were enroled in an infancy iron-deficiency anaemia preventive trial and follow-up studies at the Institute of Nutrition and Food Technology, University of Chile, Santiago, Chile. In the 577 adolescents who were assessed as part of the 16-year follow-up, we evaluated independent associations between adiponectin levels and metabolic disturbances during adolescence. We also assessed the association between early life factors [short breastfeeding {<6 months} and infancy weight gain] and adolescent adiponectin levels. Participants were 16.8 years old (16.4-18.1), 48% female and 38% overweight/obese. Adolescent adiponectin levels were inversely associated with metabolic disturbances: altered homeostatic model assessment of insulin resistance and high-density lipoprotein cholesterol [odds ratios {95% confidence interval} = 0.87 {0.79-0.95}, p-value = 0.002, and 0.90 {0.87-0.94}, p-value < 0.001, respectively], adjusting for sex and fat mass index. Early life factors were independently associated with adolescent adiponectin levels, which decreased 0.88 ug mL-1 per each unit increase in weight-for-age z-score between 0 and 6 months and was 1.58 ug mL-1 lower among participants with short breastfeeding. Higher adolescent adiponectin levels were independently associated with lower odds of metabolic disturbances. Greater weight gain during infancy and shorter breastfeeding were associated with lower adolescent adiponectin levels, supporting research indicating early life as a window of opportunity for prevention of later cardiovascular alterations. © 2017 World Obesity Federation.


Independence of the central nervous and the peripheral renin-angiotensin systems in the dog.
What regulates the activity of the central nervous renin-angiotensin system is not known. To define whether control of this central system is linked to that in the periphery, simultaneous blood and cerebrospinal fluid (CSF) samples for measurement of immunoreactive angiotensin II were drawn from anesthetized dogs during hemorrhage, furosemide-induced volume depletion, insulin-hypoglycemia, beta-adrenergic blockade and saline infusion. Despite vigorous increments or decrements in plasma innunoreactive angiotensin II, CSF levels remained stable. Since immunoreactive angiotensin II in dog CSF is claimed to be mainly the heptapeptide des-Asp1-angiotensin II (angiotensin III), the possibility that the level of this peptide within CSF simply reflects plasma concentrations was assessed by infusing angiotensin III (2.5 and 25 ng/kg/min intravenously, each for 60 minutes) and monitoring plasma and CSF peptide levels. Whereas plasma immunoreactive angiotensin II levels increased appropriately across the infusions, no change in CSF levels was observed. These studies indicate the angiotensin III does not cross the blood-CSF barrier, at least in the short term.


[Results of sanitary epidemiologic examination of sanitary protective zone projects (discussion).
The authors defined main transgressions of law in sanitary epidemiologic well-being of population during sanitary epidemiologic examination of project materials for sanitary protective zones for enterprises, constructions and other objects, and during determination of their final dimensions.


The activation of gene expression and alternative splicing in the formation and evolution of allopolyploid Brassica napus.
Allopolyploids contain two or more sets of subgenomes. To establish a compatible relationship between subgenomes, a series of gene expression changes occurred in allopolyploids. What evolutionary changes of transcripts have taken place in Brassica napus during the early establishment and subsequent evolution was a fascinating scientific question. Here, we study this issue using a set of materials (natural, resynthesized B. napus and their progenitors/parents) by long-read RNA sequencing technology. The results showed that more genes were up-regulated in resynthesized B. napus compared with its two parents, and more up-regulated expressed genes were observed in natural B. napus compared with resynthesized B. napus. The presence of up-regulation genes in organism may help it adapt to the influence of "genomic shock" and cope with natural environment. Isoforms are produced from precursor mRNAs by alternative splicing (AS) events, and more than 60% of novel isoforms were identified in all materials, which could improve the reference genome information of B. napus. We found that the isoform numbers, the number of genes potentially involved in AS and alternative polyadenylation increased in B. napus after evolution, which may involve in the adaptation of plants to natural environment. In addition, all identified isoforms were functional annotated by searching 7 databases. In general, this study could improve our overall understanding of the full-length transcriptome of B. napus, and help us recognize the significant gene expression changes and isoform abundance changes occurred in allopolyploid B. napus during evolution.


In silico simulations reveal that RYR distribution affects the dynamics of calcium release in cardiac myocytes.
The dyads of cardiac myocytes contain ryanodine receptors (RYRs) that generate calcium sparks upon activation. To test how geometric factors of RYR distribution contribute to the formation of calcium sparks, which cannot be addressed experimentally, we performed in silico simulations on a large set of models of calcium release sites (CRSs). Our models covered the observed range of RYR number, density, and spatial arrangement. The calcium release function of CRSs was modeled by RYR openings, with an open probability dependent on concentrations of free Ca2+ and Mg2+ ions, in a rapidly buffered system, with a constant open RYR calcium current. We found that simulations of spontaneous sparks by repeatedly opening one of the RYRs in a CRS produced three different types of calcium release events (CREs) in any of the models. Transformation of simulated CREs into fluorescence signals yielded calcium sparks with characteristics close to the observed ones. CRE occurrence varied broadly with the spatial distribution of RYRs in the CRS but did not consistently correlate with RYR number, surface density, or calcium current. However, it correlated with RYR coupling strength, defined as the weighted product of RYR vicinity and calcium current, so that CRE characteristics of all models followed the same state-response function. This finding revealed the synergy between structure and function of CRSs in shaping dyad function. Lastly, rearrangements of RYRs simulating hypothetical experiments on splitting and compaction of a dyad revealed an increased propensity to generate spontaneous sparks and an overall increase in calcium release in smaller and more compact dyads, thus underlying the importance and physiological role of RYR arrangement in cardiac myocytes.


Hydroxyapatite deposition disease (HADD) of the spring ligament: an unusual cause of medial foot pain.
Foot pain is one of the most common presenting complaints in orthopaedic clinical practice and can be attributed to a multitude of pathologies in the various osseous structures, ligaments, and tendons of the foot. The spring ligament complex (SLC) between the calcaneum and navicular supports the talus and plays a major role in the static stability of the medial longitudinal arch of the foot. Although calcific ligamentous enthesopathy around the ankle has been described in the literature, we report the first case of its kind affecting the SLC in a 51-year-old male with medial foot pain and no history of trauma. We highlight the role of radiological interventions in the diagnosis and effective management using ultrasound (US)-guided barbotage.


High-density apolipoprotein A-I and A-II kinetics in relation to regional adiposity.
High-density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I concentrations decrease with increasing central adiposity. The present study investigated possible mechanisms for these effects by examining the relationship between body mass index, regional adiposity, and HDL apo A-I and A-II metabolism. Fifteen sedentary men and 10 male endurance athletes aged 22 to 44 served as subjects. HDL apo A-I and A-II metabolism was examined using 125I-labeled autologous HDL. Chest and thigh skinfold thickness and the ratio of chest to thigh skinfold thickness were used as indices of regional adiposity. The relationship of adiposity to HDL metabolism was examined using correlational and multiple regression analysis. In both subject groups, the fractional catabolic rate of apo A-I and A-II increased with increasing chest skinfold thickness and chest to thigh skinfold ratio (.43 < r2 < .66). This effect was partially independent of triglyceride or HDL cholesterol concentrations. Apo A-I and A-II fractional catabolic rates increased with increasing body mass index only in the sedentary men. Concentrations and synthetic rates (mg.d-1.kg-1) of apo A-I and A-II were not consistently related to body mass index or regional adiposity. Peripheral adiposity assessed by thigh skinfold thickness was not correlated with any parameter of apo metabolism. We conclude that HDL apo A-I and A-II catabolism increases with increasing central adiposity.


Addressing Social Determinants of Health to Reduce Disparities Among Individuals with Cancer: Insights for Rehabilitation Professionals.
This report aims to provide a framework for cancer rehabilitation professionals to assess social determinants of health in individuals with cancer and discuss strategies that can be implemented in practice to overcome barriers to care. There has been an increased focus in improving patient conditions that can affect access to cancer rehabilitation. Along with government and world health organization initiatives, healthcare professionals and institutions continue to work towards decreasing disparities. Several disparities exist in healthcare and education access and quality, patients' social and community context, neighborhood and built environments, and economic stability. The authors emphasized the challenges that patients who require cancer rehabilitation face that healthcare providers, institutions, and governments can mitigate with outlined strategies. Education and collaboration are essential to make true progress in decreasing disparities in the populations most in need.


Phosphofructokinase activity in the preimplantation mouse embryo.
Phosphofructokinase activity remains relatively constant during the preimplantation period in the mouse, with a low point at day 4 (approximately 3.0×1-11 moles of substrate converted per embryo per hour).


Performance on the Wechsler Adult Intelligence Scale (WAIS) in Japanese patients with bipolar and major depressive disorders in euthymic and depressed states.
This study aimed to examine the cognitive performance of patients with bipolar disorder (BD) stratified by illness phase compared to that of patients with major depressive disorder (MDD) and healthy controls. Participants were 139 patients with BD (55 euthymic and 84 depressed), 311 patients with MDD (88 euthymic and 223 depressed), and 386 healthy controls who underwent the Wechsler Adult Intelligence Scale-Revised or the Third Edition. They were non-elderly Japanese individuals with normal estimated premorbid intelligence quotient (IQ; >90), group-matched for age, sex, and premorbid IQ. The depressed BD group showed significantly lower scores on verbal IQ, performance IQ, full-scale IQ, and three group indexes of perceptual organization, working memory, and processing speed when compared with healthy controls (all P < 0.001). All IQs and working memory index were also significantly lower than those of the depressed MDD group. The depressed MDD group scored significantly lower than controls in performance IQ (P < 0.001), full-scale IQ, and only in the index of processing speed (P < 0.001). The euthymic BD group scored significantly lower than controls in performance IQ (P = 0.004), whereas the euthymic MDD group scored significantly lower than controls only in processing speed (P = 0.030). Patients with BD appear to have global and more intense cognitive impairments in depressed states compared with those with MDD whose impairments seem to be apparent only in processing speed in the Wechsler Adult Intelligence Scale. Attenuated impairments appear to exist in euthymic states of both patients.


The rule of fives, a simple way to stratify risk for primary gastrointestinal stromal tumors (GIST).
The current AJCC version 7 staging system is a lugubrious means to classify gastrointestinal stromal tumors with respect to their risk and need for adjuvant systemic therapy. The rule of fives, suggested here, is a means to quickly assess whether a given gastrointestinal stromal tumor is low vs intermediate-high risk.


Lysophosphatidylcholine: essential role in the inhibition of endothelium-dependent vasorelaxation by oxidized low density lipoprotein.
Endothelial cells are known to play an important role in the regulation of vascular tone. Here we demonstrate that modified low density lipoprotein (LDL) with copper oxidation or phospholipase A2 treatment elicits a potent inhibitory action on endothelium-dependent relaxations evoked by acetylcholine, although native LDL does not affect endothelium-dependent relaxations. Phosphatidylcholine of native LDL is converted to lysophosphatidylcholine during these modifications. Furthermore, lysophosphatidylcholine fraction separated from oxidized LDL (0.5mg.protein/ml) by thin layer chromatography abolished endothelium-dependent relaxations, although the remaining lipid fraction had little effects on endothelium-dependent relaxations. These results indicate that lysophosphatidylcholine is the principal substance for the impairment of endothelium-dependent relaxations by oxidized LDL and phospholipase A2 treated LDL.


A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Eastern European Study Group.
Efficacy and safety of toremifene 60 and 240 mg daily (TOR60 and TOR240) are compared to 40 mg tamoxifen daily (TAM40) in postmenopausal women with advanced estrogen receptor (ER) positive or ER unknown breast cancer. The study is randomized and open label in three parallel groups. Primary efficacy variables are response rate and time to progression. WHO and ECOG criteria were used for measurable and nonmeasurable disease assessment, respectively. Safety was reported according to WHO criteria. Altogether 463 patients were randomized (157 to TOR60, 157 to TOR240, and 149 to TAM40). By data cut-off, after 20.5 months median follow-up time, over 70% of the patients had experienced disease progression. Response rates are 20.4%, 28.7%, and 20.8% in TOR60. TOR240, and TAM40, respectively. TOR60 and TAM40 show statistically equivalent efficacy and the difference between TOR240 and TAM40 is not significant (P = 0.112). Median times to progression are 4.9 (TOR60), 6.1 (TOR240), and 5.0 (TAM40) months and the corresponding hazard ratios (TAM:TOR) 1.015 and 1.124. Again, TOR60 and TAM40 are statistically equivalent and the difference between TOR240 and TAM40 is not significant (P = 0.374). All treatments were well tolerated. As a conclusion, TOR60 and TAM40 show equivalent clinical efficacy and tolerability. The higher dose of toremifene slightly but not statistically significantly improves response rate and time to progression. In postmenopausal women, toremifene 60 mg daily is an effective and safe treatment of advanced ER-positive or ER-unknown breast cancer.


[Influenza, tetanus, and pertussis vaccination coverage among adults in Germany].
In order to be adequately protected throughout life and to protect specific risk groups from particular diseases, regular booster or specific indicator vaccinations are also recommended during adulthood. Adults should be vaccinated against seasonal influenza (annually, e.g., persons with underlying chronic diseases and persons aged ≥ 60 years), tetanus (every 10 years), and pertussis (as a one-time vaccination with the next due tetanus vaccine and, e.g., when people have close contact to newborn babies). The aim of this study was to provide an overview of the current status of vaccination uptake among adults living in Germany, focusing on these three vaccines. In line with nationwide continuous health monitoring, the Robert Koch Institute conducted the representative study "German Health Update" (GEDA 2012) between 2012 and 2013. The survey is conducted regularly and adults are asked questions relating to their vaccination status through computer-assisted telephone interviews. Overall, 19,294 interviews were held. In 2010/2011 and 2011/2012, seasonal influenza uptake among persons aged ≥ 60 years was 54.3 and 52.6 % and among individuals with underlying chronic diseases 46.2 and 42.9 %. 7.6 and 75.6 % of participants reported up-to-date pertussis and tetanus vaccination, respectively. 22 % of people living with a baby in one household were vaccinated against pertussis. In general, vaccination rates against seasonal influenza, pertussis, and tetanus among adults are still low, but differ depending on the specific vaccination. The required aim of the European Commission to reach influenza vaccination coverage by the 2014/2015 winter season of 75 % of higher age groups has not yet been reached. The low pertussis vaccination coverage among persons in close household contact to infants poses a big challenge to the implementation of the cocooning strategy to protect the very vulnerable newborns. To emphasize the importance of a complete vaccination schedule and to increase vaccination uptake, tailored interventions should be provided for both physicians and adults.


Novel photosensitive dual-anisotropic conductive Janus film endued with magnetic-luminescent properties and derivative 3D structures.
A new photosensitive dual-anisotropic conductive Janus film (PDCJF) is proposed for the first time. It is rationally designed and manufactured by facile electrospinning. PDCJF is firstly constructed using 2,7-dibromo-9-fluorenone (DBF) with photoconductive and luminescent properties. Janus nanofibers are respectively used as the building units to construct the top layer (T-PDCJF) and the bottom layer (B-PDCJF) of PDCJF. The two layers are tightly bonded to form PDCJF. Under light irradiation, there is photosensitive dual-anisotropic conduction in PDCJF, but there is no anisotropic conduction without light. Thus, the transition of PDCJF from mono-functional magnetism to tri-functionalities is realized under light and without light. The luminescence color of PDCJF is tunable and it emits white-light. This is made possible by modulating the amounts of luminescent substances and excitation wavelength. The microscopic Janus nanofibers used as building units and macroscopic Janus film structure ensure high photosensitive dual-anisotropic conduction and excellent fluorescence in PDCJF. The two-dimensional (2D) PDCJF is rolled to obtain three-dimensional (3D) Janus-type tubes and 2D plus 3D complete flag-like structures with exceptional multi-functionalities. The new findings can strongly guide in developing advanced multi-functional nanostructures.


Making sense of the beta-agonist debate: a guide for nurse practitioners.
This article discusses the controversy surrounding the role of beta-agonist use in asthma therapy. Historic issues that led to the controversy are initially reviewed. Current research regarding beta-agonist use is examined, and a discussion on recommendations for patient care is provided.


APC mutations in synovial sarcoma.
It has previously been demonstrated that accumulated beta-catenin serves as an oncoprotein in synovial sarcoma and results in a poor overall survival rate, but the frequency of beta-catenin mutation was quite low (8.2%). The present study, using essentially the same study group of cases, screened for genetic alterations in the mutation cluster region (MCR) of the APC gene in 49 cases of synovial sarcoma. SSCP analysis followed by DNA direct sequencing revealed five missense APC mutations in four cases of synovial sarcoma (8.2%). The mutational sites comprised one case each at codons 1299 (GCT to ACT, Ala to Thr), 1412 (GGA to AGA, Gly to Arg), and 1414 (GTA to ATA, Val to Ile), in addition to one case with double point mutations at codon 1398 (AGT to AAT, Ser to Asn) and at codon 1413 (ATG to ATA, Met to Ile), together with beta-catenin mutation at codon 32 (GAC to TAC, Asp to Tyr). All four cases with APC mutations were histologically of the monophasic fibrous type and showed beta-catenin accumulation. All three cases with APC mutations available for follow-up data were long survivors. This study provides the first evidence that APC mutations also occur in the field of sarcoma, especially in synovial sarcoma.


Class II Division 1 malocclusion treatment with extraction of maxillary first molars: Evaluation of treatment and post-treatment changes by the PAR Index.
To investigate occlusal result and post-treatment changes after orthodontic extraction of maxillary first permanent molars in patients with a Class II division 1 malocclusion. Retrospective longitudinal study in a private practice, with outcome evaluation by an independent academic hospital. Ninety-six patients (53 males, 43 females) consecutively treated by one orthodontist with maxillary first permanent molar extraction were studied, divided into three facial types, based on pre-treatment cephalometric values: hypodivergent (n = 18), normodivergent (n = 21) and hyperdivergent (n = 57). Occlusal outcome was scored on dental casts at T1 (pre-treatment), T2 (post-treatment) and T3 (mean follow-up 2.5 ± 0.9 years) using the weighted Peer Assessment Rating (PAR) Index. The paired sample t test and one-way ANOVA followed by Tukey's post hoc test were used for statistical analysis. PAR was reduced by 95.7% and 89.9% at T2 and T3, respectively, compared with the start of treatment. The largest post-treatment changes were found for overjet and buccal occlusion. Linear regression analysis did not reveal a clear effect (R-Square 0.074) of age, sex, PAR score at T1, incremental PAR score T2-T1, overjet and overbite at T1, and facial type on the changes after treatment (incremental PAR score T3-T2). The occlusal outcome achieved after Class II division 1 treatment with maxillary first permanent molar extractions was maintained to a large extent over a mean post-treatment follow-up of 2.5 years. Limited changes after treatment were found, for which no risk factors could be discerned.


Protection from sun exposure in US white children ages 6 months to 11 years.
To estimate the prevalence of protection from sun exposure among US white children ages 6 months to 11 years. During the summer of 1998, using telephone directory lists supplemented by random-digit dialing, the authors surveyed parents living in the contiguous United States. They calculated weighted prevalence estimates for protection methods and conducted logistic regression analyses to determine parent and child characteristics predictive of protection behaviors. Parents of 1,055 white children were interviewed. Children spent a median of 20 hours per week outdoors during the summer, of which 10 hours were at school. Sunscreen (61.8%, 95% confidence interval [CI] 57%, 66%) and shade (26.5%, 95% CI 22%, 31%) were the most frequently reported protection methods. Parents reported higher rates of protection for younger children and children who sunburn easily. Parents report that a large proportion of white children is protected from sun exposure by one or more methods. Health care providers and educators might encourage the use of all methods of protection, not just sunscreen use, and educate older children to protect themselves from the sun.


A case of statin-induced liver injury with positive rechallenge with a second statin. Is there a class effect?
Statins have proved to reduce cardiovascular morbidity and mortality in high-risk population and are generally well tolerated, although adverse events can occur. Up to 3% of patients develop aminotransferases elevation, which usually normalizes with continued treatment and hardly is associated with clinical symptoms. Serious statin-related liver injury is exceedingly rare. Furthermore, literature regarding rechallenge with a second statin is extremely poor. Some authors caution that re-exposure to these drugs is associated with a more serious liver injury but safe switching to a second statin after drug-induced liver injury (DILI) is also reported. We describe a case of a middle-aged woman who developed hepatocellular liver injury after simvastatin dose escalation; a rechallenge with low dose rosuvastatin caused rapid recurrence of DILI. In our opinion, clinicians should be very cautious upon rechallenge and closely follow-up patients who experienced statin-induced liver injury when trying re-exposure to another statin.


Quantitative 3D Ultrashort Echo Time Magnetization Transfer Imaging for Evaluation of Knee Cartilage Degeneration In Vivo.
Recent studies suggest that macromolecular fraction (MMF) derived from three-dimensional ultrashort echo time magnetization transfer (UTE-MT) imaging is insensitive to the magic angle effect. However, its clinical use in osteoarthritis (OA) remains to be investigated. To investigate the feasibility of 3D UTE-MT-derived MMF in differentiating normal from degenerated cartilage. Prospective. Sixty-two participants (54.8 ± 16.7 years, 30 females) with and without OA, plus two healthy volunteers (mean age 35.0 years) for reproducibility test. 3 T/UTE-MT sequence. A 3D UTE-MT sequence was employed to calculate MMF based on a two-pool model. Kellgren-Lawrence (KL) grade and Whole-Organ Magnetic Resonance Imaging Score (WORMS) were evaluated by three experienced musculoskeletal radiologists. KL grade was condensed into three groups: KL0, KL1-2, and KL3-4. WORMS was regrouped based on extent of lesion (extent group) and depth of lesion (depth group), respectively. The performance of MMF at evaluating the degeneration of cartilage was assessed via Spearman's correlation coefficient and the area under the curve (AUC) calculated according to the receiver-operating characteristic curve. After normality check, one-way analysis of variance was used to evaluate the performance. Tukey-Kramer test was performed for post hoc testing. MMF showed significant negative correlations with KL grade (r = -0.53, P < 0.05) and WORMS (r = -0.49, P < 0.05). Significantly lower MMFs were found in subjects with greater KL grade (11.8 ± 0.8% for KL0; 10.9 ± 0.9% for KL1-2; 10.6 ± 1.1% for KL3-4; P < 0.05) and in cartilage with greater extent (12.1 ± 1.6% for normal cartilage; 10.9 ± 1.6% for regional lesions; 9.6 ± 1.7% for diffuse lesions; P < 0.05) and depth (12.1 ± 1.6% for normal cartilage; 10.6 ± 1.6% for partial-thickness lesions; 8.8 ± 1.7% for full-thickness lesions; P < 0.05) of lesions. AUC values of MMF for doubtful-minimal OA (KL1-2) and mild cartilage degradation (WORMS1-2) were 0.8 and 0.7, respectively. This study highlights the clinical potential of MMF in the detection of early OA. 2 TECHNICAL EFFICACY STAGE: 2.


Interferon enhances T cell mediated cytotoxicity of H-2 compatible target cells infected with UV-inactivated herpes simplex virus.
Mouse L-cells infected with UV-inactivated HSV could serve as suitable targets for monitoring H-2 restricted cytotoxicity mediated by HSV-immune T cells. Cytotoxic potential of immune T cells for H-2 compatible targets exposed to UV-inactivated HSV was enhanced if the later were pretreated with mouse interferon.


Evolution of the two-week rule pathway--direct access colonoscopy vs outpatient appointments: one year's experience and patient satisfaction survey.
Abstract Objectives The aim of this study was to compare the effectiveness of Direct access colonoscopy (DAC) vs outpatient appointments for two-week rule colorectal cancer referrals and to evaluate the satisfaction of patients referred through these routes. Patients and methods Data were collected prospectively from January 2003 to December 2003 on patients who were referred for DAC or outpatient appointments at the discretion of the referring General practitioner via the Lower GI two-week rule pathway. A postal questionnaire was used to survey patient satisfaction. Results Six hundred and thirty-nine patients were referred via the two-week rule pathway; 188 patients underwent colonoscopy at their initial hospital visit and 19 (10.1%) colorectal cancers were diagnosed; 442 patients had an outpatient appointment and 32 (7.2%) colorectal cancers were identified. There were 7 (1%) inappropriate referrals and 2 patients refused investigations. All outcome parameters measured were reduced for patients referred directly for colonoscopy including time to definitive investigations (Median 9 vs 52 days P < 0.0001), time to histological diagnosis (Median 14 vs 42 days P < 0.0001) and time to treatment (Median 55 vs 75 days P < 0.0483). One hundred and seventy patients were surveyed by the postal questionnaire of whom 127 (75%) responded. Ninety-eight percent of patients were satisfied with the service provided. Four (6.6%) of 60 patients who had undergone direct access colonoscopy expressed a desire to be seen at the outpatient department initially. Conclusions Direct access colonoscopy results in significantly reduced times to histological diagnosis and definitive treatment in patients with colorectal cancer. Patients can be directly admitted for investigations bypassing the outpatient clinic without affecting patient satisfaction.


A patient-focused, theory-guided approach to survey design identified barriers to and drivers of clinical trial participation.
Despite clear evidence showing that many clinical trials fail or are delayed because of poor patient recruitment, there is surprisingly little empirically supported guidance for trialists seeking to optimize their trial recruitment strategies. We propose that the challenges of recruitment can be better understood and addressed by thinking of research participation as one or more behaviors, subject to the same forces as other human behaviors. In this article, we describe an adaptable, behavioral theory-driven approach for designing pretrial surveys of the barriers and drivers relevant to trial participation. Instead of proposing a single survey instrument intended to be used uniformly across many situations, we propose that tailored surveys be informed by a common comprehensive, theory-guided development approach that ensures all domains potentially guiding participation are considered. We used the Theoretical Domains Framework (TDF), which organizes over 100 constructs known to be associated with behavior and behavior change into 14 domains that describe determinants of professional and patient health behaviors, to inform the development of tailored surveys about barriers to and drivers of clinical trial participation. After searching the literature for barriers and drivers to trial recruitment relevant to each of the TDF domains, we developed separate surveys for members of two national health charities (Canadian Breast Cancer Network, Huntington Society of Canada) to exemplify how the approach can be adapted across settings. We conducted think-aloud interviews with members of each group to maximize the clarity and usability of the surveys, elicited opinions about which barriers/drivers were relevant for each patient group, and identified additional barriers/drivers. Interviews proceeded iteratively with changes incorporated into subsequent interviews. Here, we describe our two target patient groups, as well as our process of modifying, adding, and deleting barrier/driver items for each group and across theoretical domains. We interviewed 8 women with a history of breast cancer from the Canadian Breast Cancer Network (48-65 year old) and 11 Huntington Disease community members (9 women) from the Huntington Society of Canada (26-70 year old). After the iterative development interviews, the breast cancer group had identified 38 barriers/drivers thought relevant to their participation in clinical trials across 12 TDF domains. The Huntington group identified 47 items across 13 TDF domains. Our patient-focused and theory-guided approach was able to identify a more comprehensive range of barriers to and drivers of trial participation than existing published tools. Our approach is also more broadly adaptable than such tools, in that it uses a theoretical framework and in-depth piloting to generate a set of items tailored to each specific clinical area, rather than a single set of items intended to be applicable to all situations. This theory-guided approach also enables more specific recruitment strategies to be developed once domain-specific barriers are known, potentially optimizing participation for a given trial and helping build a cumulative evidence of barriers/drivers and strategies for addressing them.


Carcinogenicity, efficiency and biosafety analysis in xeno-free human amniotic stem cells for regenerative medical therapies.
Human amniotic mesenchymal stromal cells (hAMSCs) are a potent and attractive stem cell source for use in regenerative medicine. However, the safe uses of therapeutic-grade MSCs are equally as important as the efficiency of MSCs. To provide efficient, clinic-compliant (safe for therapeutic use) MSCs, hAMSC lines that completely eliminate the use of animal products and have been characterized for carcinogenicity and biosafety are required. Here, we have efficiently generated 10 hAMSC lines under human umbilical cord blood serum (hUCS)-supplemented medium (xeno-free culture) and fetal bovine serum (FBS)-supplemented medium (standard culture) and investigated carcinogenicity and immunosuppressive properties in the resultant hAMSC lines. All hAMSC lines were examined for efficiency (growth kinetics, cryopreservation, telomere length, phenotypic characterization, differentiation potential), carcinogenicity (proto-oncogene and tumor suppressor gene and epigenomic stability) and safety (immunosuppressive properties). Stem cell characteristics between the xeno-free hAMSC lines and the cell lines generated using the standard culture system showed no differences. Xeno-free hAMSC lines displayed normal growth proliferation potential, morphological, karyotypic, phenotypic differentiation properties and telomere lengths. Additionally, they retained normal immunosuppressive effects. As a marker of carcinogenicity and biosafety, proto-oncogenes expression levels showed no differences in xeno-free hAMSCs, and we detected no SNP mutations on hotspot codons of the P53 tumor suppressor gene and stable epigenomic imprinting in xeno-free hAMSC lines. Xeno-free hAMSC lines retain essential stem cell characteristics, with a high degree of certainty for meeting biosafety and carcinogenicity standards for a xeno-free system supplemented with allogenic hUCS. The cell lines are suitable and valuable for therapeutic purposes.


Reduction of morphine-withdrawal aggression by conditional social stimuli.
Sixty male hooded rats were made physically dependent on morphine by steadily increasing doses of morphine sulphate. A maintenance dose of 400 mg/kg/day was reached in 10 days and was continued for 5 additional days. At the end of the 15-day period all rats were withdrawn for 72 h and aggressive responses (attacks, rearing, and vocalization) were recorded for a 60-min period. One treatment group, in which a social experience had been paired with each morphine injection, showed significantly less morphine-withdrawal aggression than rats in two other groups which either remained socially isolated throughout the addiction period, or were grouped both at the time of morphine injection and during between-injection intervals.


Uniaxial mechanical strain: an in vitro correlate to distraction osteogenesis.
Distraction osteogenesis is a valuable clinical tool; however the molecular mechanisms governing successful distraction remain unknown. We have used a uniaxial in vitro strain device to simulate the uniaxial mechanical environment of the interfragmentary distraction gap. Using the Flexcell system, normal human osteoblasts were subjected to different levels of cyclical uniaxial mechanical strain. Cellular morphology, proliferation, migration, and the expression of angiogenic (vascular endothelial growth factor [VEGF] and fibroblast growth factor-2 [FGF-2]) and osteogenic (osteonectin, osteopontin, and osteocalcin) proteins and extracellular matrix molecules (collagen IalphaII) were analyzed in response to uniaxial cyclic strain. Osteoblasts exposed to strain assumed a fusiform spindle-shaped morphology aligning parallel to the axis of uniaxial strain and osteoblasts exposed to strain or conditioned media had a 3-fold increase in proliferation. Osteoblast migration was maximal (5-fold) in response to 9% strain. Angiogenic cytokine, VEGF, and FGF-2, increased 32-fold and 2.6-fold (P < 0.05), respectively. Osteoblasts expressed greater amounts of osteonectin, osteopontin, and osteocalcin (2.1-fold, 1.8-fold, 1.5-fold respectively, P < 0.01) at lower levels of strain (3%). Bone morphogenic protein-2 production increased maximally at 9% strain (1.6-fold, P < 0.01). Collagen I expression increased 13-, 66-, and 153-fold in response to 3, 6, and 9% strain, respectively. Uniaxial cyclic strain using the Flexcell device under appropriate strain parameters provides a novel in vitro model that induces osteoblast cellular and molecular expression patterns that simulate patterns observed in the in vivo distraction gap.


Tissue Trauma after Laparoscopic and Abdominal Hysterectomy Measuring Inflammatory Response
It is suggested that laparoscopic surgery reduces postoperative pain and shortens hospital stay and convalescence because of the small amount of tissue trauma. We evaluated the inflammatory response during abdominal hysterectomy (AH, 12 women) and laparoscopic hysterectomy (LH, 12 women) by measuring interleukin (IL)-6, neopterin and terminal C5b9 complement complex (TCC). Blood samples were drawn preoperatively, perioperatively, 1 minute, 24 hours, and 7 days postoperatively. Levels of IL-6 were determined to evaluate cytokine release, neopterin was determined as a marker for macrophage-monocyte activation, and TCC was determined to assess complement activation. The IL-6 concentrations, as a percentage of preoperative level, were significantly elevated postoperatively in both groups, and also perioperatively in the LH group. Neopterin concentrations, as a percentage of perioperative level, were significantly increased in the LH group preoperatively and postoperatively. No elevation was seen in the AH group. There was no sign of complement activation in either group. Our results indicate significant tissue trauma during both LH and AH. The extent of trauma might be greater in laparoscopic surgery. Despite this, the LH group had a shorter hospital stay and convalescence than the AH group. The proposed advantages to the patient of laparsocopic surgery thus seem to be attributable to other factors than the amount of tissue trauma.


[Radiocarpal reconstruction by island transfer of the distal radio-ulnar joint].
We described the island transfer of the DRUJ to reconstruct the radiocarpal joint when the radiocarpal and the mediocarpal joints are destroyed. The objective is to avoid wrist arthrodesis or prosthesis. From 1993 to 1997, five patients were operated, five men, the average age was 55 years (36 to 67). The operated side was the dominant side one time. The joint destruction was secondary to: SLAC wrist (stage 3) in two cases, a failure of PRC in two cases and post-traumatic necrosis of the lunatum in one case. One failure was resumed by total wrist arthrodesis at 1-year follow-up. Four patients were revised with 11 years follow-up (from nine to 13). Two patients presented a pain-free wrist, two patients complain of barometric pain or after heavy works. The average mobility was: extension 40°, flexion 25°, ulnar deviation 30°, radial deviation -3°, complete pronosupination. The strength was 65% of the opposite side. X-rays showed an important radiocarpal reshaping and ulnar sliding of the carpus. The island transfer of the DRUJ was possible in every case. The discordance between clinical and radiological results can be explained by joint denervation. We stopped this procedure not to sacrifice any more the healthy DRUJ. The island transfer of the DRUJ to reconstruct the radiocarpal joint is a solution to avoid total wrist arthrodesis or prosthesis if we accept the DRUJ sacrifice.


How best to approach endoscopic sedation?
Sedation is the drug-induced reduction of a patient's consciousness. The aim of sedation in endoscopic procedures is to increase the patient's comfort and to improve endoscopic performance, especially in therapeutic procedures. The most commonly used sedation regimen for conscious sedation in gastrointestinal endoscopy is still the combination of benzodiazepines with opioids. However, the use of propofol has increased enormously in the past decade and several studies show advantages of propofol over the traditional regimes in terms of faster recovery time. It is important to be aware that the complication rate of endoscopies increases when sedation is used; therefore, a thorough risk evaluation before the procedure and monitoring during the procedure must be performed. In addition, properly trained staff and emergency equipment should be available. The best approach to sedation in endoscopy is to choose a sedation regimen for the individual patient, tailored according to the clinical risk assessment and the anxiety level of the patient, as well as to the type of planned endoscopic procedure.


Effects of removing extracellular Ca2+ on excitation and adaptation in Limulus ventral photoreceptors.
In Limulus ventral photoreceptors, removing extracellular calcium (Ca2+o) increases the median latency of light-evoked discrete waves. Removal greatly lengthens the time-to-peak of responses in the dark-adapted cell, but not in the light-adapted cell. Removal does not block light-adaptation or the light-induced rise in intracellular calcium (Ca2+i). These results are interpreted in terms of the hypothesis that both sensitivity and the kinetics of excitation are dependent on Ca2+i, and that Ca2+i is dependent on Ca2+o in the dark-adapted cell, but in the light is dependent largely on Ca2+ released from intracellular compartments.


FOSL2 promotes intertumoral infiltration of T cells and increases pathological complete response rates in locally advanced rectal cancer patients.
The outcome of neoadjuvant chemoradiotherapy (nCRT) remains highly unpredictable for individuals with locally advanced rectal cancer (LARC). We set out to characterize effective biomarkers that promote a pathological complete response (pCR). We quantified the abundances of 6483 high-confidence proteins in pre-nCRT biopsies of 58 LARC patients from two hospitals with pressure cycling technology (PCT)-assisted pulse data-independent acquisition (PulseDIA) mass spectrometry. Compared with non-pCR patients, pCR patients achieved long-term disease-free survival (DFS) and had higher tumor immune infiltration, especially CD8+ T cell infiltration, before nCRT. FOSL2 was selected as the candidate biomarker for predicting pCR and was found to be significantly upregulated in pCR patients, which was verified in another 54 pre-nCRT biopsies of LARC patients by immunohistochemistry. FOSL2 expression was able to predict pCR by multiple reaction monitoring (MRM) with high efficiency (Area under curve (AUC) = 0.939, specificity = 1.000, sensitivity = 0.850), and high FOSL2 expression was associated with long-term DFS (p = 0.044). When treated with simulated nCRT, FOSL2 sufficiency resulted in more significant inhibition of cell proliferation, and more significant promotion of cell cycle arrest and cell apoptosis. Moreover, CXCL10 secretion with abnormal cytosolic dsDNA accumulation was found in FOSL2-wildtype (FOSL2-WT) tumor cells over nCRT, which might elevate CD8+ T-cell infiltration and CD8+ T-cell-mediated cytotoxicity to promote nCRT-induced antitumor immunity. Our study revealed proteomic profiles in LARC patients before nCRT and highlighted immune activation in the tumors of patients who achieved pCR. We identified FOSL2 as a promising biomarker to predict pCR and promote long-term DFS by contributing to CD8+ T-cell infiltration.


Cooled storage of semen from livestock animals (Part II): Camelids, goats, and sheep.
This review is part of the Festschrift in honor of Dr. Duane Garner and provides an overview of current techniques in cooled storage of semen from livestock animals such as camelids, goats, and sheep. Facing worldwide environmental changes and a trend towards more conscious and healthy eating behaviors, the development of a stable animal breeding industry is a significant challenge for the near future. In the present review, factors influencing semen handling in camelids, goats and sheep are described and relevant methods as well as current trends to improve liquid-storage of cooled semen are discussed, including extenders, additives, cooling rates, and storage temperatures. The species-specific physiology and resulting challenges are taken into consideration. While the main problem for camelid semen processing is the relatively greater viscosity as compared with that of some other animals, the deciding factor for successful artificial insemination (AI) in goats and sheep is the site (i.e., cervical or vaginal) of semen placement in the reproductive tract. Due to the type of cervical anatomy, the penetration of the cervix when using AI instruments is rather difficult. Furthermore, the seminal plasma of small ruminants affects the interaction with milk-based extenders and egg yolk which results in species-specific regimens for cooled liquid-preservation. Comparing all three species, the greatest pregnancy rates were obtained by AI with goat semen after cooled liquid-storage for several days.


Impaired intestinal afferent nerve satiety signalling and vagal afferent excitability in diet induced obesity in the mouse.
Gastrointestinal vagal afferents transmit satiety signals to the brain via both chemical and mechanical mechanisms. There is indirect evidence that these signals may be attenuated in obesity. We hypothesized that responses to satiety mediators and distension of the gut would be attenuated after induction of diet induced obesity. Obesity was induced by feeding a high fat diet (60% kcal from fat). Low fat fed mice (10% kcal from fat) served as a control. High fat fed mice were obese, with increased visceral fat, but were not hyperglycaemic. Recordings from jejunal afferents demonstrated attenuated responses to the satiety mediators cholecystokinin (CCK, 100 nm) and 5-hydroxytryptamine (5-HT, 10 μm), as was the response to low intensity jejunal distension, while responses to higher distension pressures were preserved. We performed whole cell patch clamp recordings on nodose ganglion neurons, both unlabelled, and those labelled by fast blue injection into the wall of the jejunum. The cell membrane of both labelled and unlabelled nodose ganglion neurons was less excitable in HFF mice, with an elevated rheobase and decreased number of action potentials at twice rheobase. Input resistance of HFF neurons was also significantly decreased. Calcium imaging experiments revealed reduced proportion of nodose ganglion neurons responding to CCK and 5-HT in obese mice. These results demonstrate a marked reduction in afferent sensitivity to satiety related stimuli after a chronic high fat diet. A major mechanism underlying this change is reduced excitability of the neuronal cell membrane. This may explain the development of hyperphagia when a high fat diet is consumed. Improving sensitivity of gastrointestinal afferent nerves may prove useful to limit food intake in obesity.


Comparison between transpapillary versus transmural endoscopic ultrasound-guided decompression for biliary obstruction: a meta-analysis.
Recent advances have led to the development of transmural endoscopic ultrasound guided biliary drainage (EUS-BD) for cases where the duodenal papilla cannot be accessed. We performed a meta-analysis comparing efficacy and complications of both approaches for biliary drainage. English articles were searched in PubMed. Primary outcomes included technical success and complications. Secondary outcomes were clinical success and subsequent stent malfunction. Patient demographics and etiology of obstruction were collected and relative risk ratios and 95% CIs were calculated. P-value <0.05 was considered as statistically significant. Initial database search yielded 245 studies from which 7 were chosen based upon inclusion criteria for final analysis. There was no statistically different relative risk for technical success when comparing primary EUS-BD to endoscopic retrograde cholangiopancreatography (ERCP) (RR: 1.04) or overall procedural complication rate (RR 1.39). EUS-BD did have increased specific risk of cholangitis (RR: 3.01). Likewise, primary EUS-BD and ERCP had similar RR for clinical success (RR: 1.02) and overall stent malfunction (RR: 1.55), but stent migration was higher in the primary EUS-BD group (RR: 5.06). Primary EUS-BD may be considered when the ampulla cannot be accessed, when there is gastric outlet obstruction, or presence of a duodenal stent.


Membrane-active antimicrobial peptides and human placental lysosomal extracts are highly active against mycobacteria.
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, manifests discreet strategies to subvert host immune responses, which enable the pathogen to survive and multiply inside the macrophages. This problem is further worsened by the emergence of multidrug resistant mycobacterial strains, which make most of the anti-tuberculous drugs ineffective. It is thus imperative to search for and design better therapeutic strategies, including employment of new antibiotics. Recently, naturally produced antimicrobial molecules such as enzymes, peptides and their synthetic analogs have emerged as compounds with potentially significant therapeutical applications. Although, many antimicrobial peptides have been identified only very few of them have been tested against mycobacteria. A major limitation in using peptides as therapeutics is their sensitivity to enzymatic degradation or inactivity under certain physiological conditions such as relatively high salt concentration. Here, we show that NK-2, a peptide representing the cationic core region of the lymphocytic effector protein NK-lysin, and Ci-MAM-A24, a synthetic salt-tolerant peptide derived from immune cells of Ciona intestinalis, efficiently kill Mycobacterium smegmatis and Mycobacterium bovis-BCG. In addition, NK-2 and Ci-MAM-A24 showed a synergistic killing effect against M. smegmatis, no cytotoxic effect on mouse macrophages at bactericidal concentrations, and were even found to kill mycobacteria residing inside the macrophages. We also show that human placental lysosomal contents exert potent killing effect against mycobacteria under acidic and reducing growth conditions. Electron microscopic studies demonstrate that the lysosomal extract disintegrate bacterial cell membrane resulting in killing of mycobacteria.


Large-scale computational discovery and analysis of virus-derived microbial nanocompartments.
Encapsulins are a class of microbial protein compartments defined by the viral HK97-fold of their capsid protein, self-assembly into icosahedral shells, and dedicated cargo loading mechanism for sequestering specific enzymes. Encapsulins are often misannotated and traditional sequence-based searches yield many false positive hits in the form of phage capsids. Here, we develop an integrated search strategy to carry out a large-scale computational analysis of prokaryotic genomes with the goal of discovering an exhaustive and curated set of all HK97-fold encapsulin-like systems. We find over 6,000 encapsulin-like systems in 31 bacterial and four archaeal phyla, including two novel encapsulin families. We formulate hypotheses about their potential biological functions and biomedical relevance, which range from natural product biosynthesis and stress resistance to carbon metabolism and anaerobic hydrogen production. An evolutionary analysis of encapsulins and related HK97-type virus families shows that they share a common ancestor, and we conclude that encapsulins likely evolved from HK97-type bacteriophages.


Gastric cancer precursor lesions and Helicobacter pylori infection in patients with partial gastrectomy for peptic ulcer.
The mucosa of the gastric stump is considered at greater risk of dysplastic and neoplastic changes than that of the intact stomach. The combination of enteric reflux and Helicobacter pylori infection may have a synergistic damaging effect on the mucosa of the gastric remnant, both producing and increasing mucosal proliferation. The aim of this study was to assess whether the occurrence of H. pylori infection in the remnant mucosa of partially gastrectomized subjects for peptic ulcer disease is associated with an increase of the mucosal precursor lesions of malignancy. A series of 151 subjects who underwent partial gastrectomy for peptic ulcer disease were submitted to upper digestive endoscopy for long-term surveillance. Biopsy specimens of the gastric stump were tested for the occurrence of H. pylori infection and for the presence of precancerous mucosal lesions. The prevalence of H. pylori colonization in the remnant stomach was less than 30% and similar in subjects with different time intervals between gastrectomy and endoscopy. Age at surgery (chi(2): p = 0.03) and H. pylori infection (chi(2): p = 0.002) were significantly associated with the grading of mucosal lesions. The prevalence of normal mucosa was 10 times higher in H. pylori-negative patients as in H. pylori-positive ones (22.0% vs. 2.4%), and the prevalence of intestinal metaplasia was four times higher in H. pylori-positive patients than in H. pylori-negative ones (19.6% vs. 4.6%). We concluded that H. pylori infection may play a causal role in the development of gastric lesions in the operated stomach.


Association between conventional risk factors and different ultrasound-based markers of atherosclerosis at carotid and femoral levels in a middle-aged population.
Ultrasound detection of sub-clinical atherosclerosis (ATS) may help identify individuals at high cardiovascular risk. Most studies evaluated intima-media thickness (IMT) at carotid level. We compared the relationships between main cardiovascular risk factors (CVRF) and five indicators of ATS (IMT, mean and maximal plaque thickness, mean and maximal plaque area) at both carotid and femoral levels. Ultrasound was performed on 496 participants aged 45-64 years randomly selected from the general population of the Republic of Seychelles. 73.4 % participants had ≥ 1 plaque (IMT thickening ≥ 1.2 mm) at carotid level and 67.5 % at femoral level. Variance (adjusted R2) contributed by age, sex and CVRF (smoking, LDL-cholesterol, HDL-cholesterol, blood pressure, diabetes) in predicting any of the ATS markers was larger at femoral than carotid level. At both carotid and femoral levels, the association between CVRF and ATS was stronger based on plaque-based markers than IMT. Our findings show that the associations between CVRF and ATS markers were stronger at femoral than carotid level, and with plaque-based markers rather than IMT. Pending comparison of these markers using harder cardiovascular endpoints, our findings suggest that markers based on plaque morphology assessed at femoral artery level might be useful cardiovascular risk predictors.


Enhanced non-eupneic breathing following hypoxic, hypercapnic or hypoxic-hypercapnic gas challenges in conscious mice.
C57BL6 mice display non-eupneic breathing and spontaneous apneas during wakefulness and sleep as well as markedly disordered breathing following cessation of a hypoxic challenge. We examined whether (1) C57BL6 mice display marked non-eupneic breathing following hypercapnic or hypoxic-hypercapnic challenges, and (2) compared the post-hypoxia changes in non-eupneic breathing of C57BL6 mice to those of B6AF1 (57BL6 dam × A/J sire) and Swiss-Webster mice, which display different ventilatory responses than C57BL6 mice. C57BL6 mice displayed marked increases in respiratory frequency and non-eupneic breathing upon return to room-air after hypoxic (10% O2, 90% N2), hypercapnic (5% CO2, 21% O2 and 74% N2) and hypoxic-hypercapnic (10% O2, 5% CO2 and 85% N2) challenges. B6AF1 mice displayed less tachypnea and reduced non-eupneic breathing post-hypoxia, whereas Swiss-Webster mice displayed robust tachypnea with minimal increases in non-eupneic breathing post-hypoxia. These studies demonstrate that non-eupneic breathing increases after physiologically-relevant hypoxic-hypercapnic challenge in C57BL6 mice and suggest that further studies with these and B6AF1 and Swiss-Webster mice will help define the genetics of non-eupneic breathing.


Erratum: Benefits of Switch from Oral to Subcutaneous Route on Adherence to Methotrexate in Patients with Rheumatoid Arthritis in Real Life Setting [Corrigendum].
[This corrects the article DOI: 10.2147/PPA.S301010.].


Validation of an automated home blood pressure measurement device in oldest-old populations.
Despite the wide use of automated devices for the self-measurement of home blood pressure (BP), no evidence is available regarding the accuracy of such devices in oldest-old populations. The aim of this study was to validate the accuracy of the automated oscillometric upper arm-cuff BP-monitoring device according to an international protocol in oldest-old individuals. In 35 participants aged over 85 years old, BP was measured on the same arm sequentially using a mercury sphygmomanometer (by two observers) and an Omron HEM-7080IC. The difference between the test device and observer measurements and associated factors were evaluated according to the International Organization for Standardization (ISO) 81060-2:2013 protocol. A total of 105 pairs (three pairs per participant) of the test device and observer BP measurements were obtained. The mean (±standard deviation: SD) differences in systolic BP (SBP) and diastolic BP (DBP) between the methods were -0.7 ± 7.1 and -1.1 ± 4.5 mmHg, respectively, and those for each participant were -0.7 ± 5.8 mmHg for SBP and -1.1 ± 4.1 mmHg for DBP; the device therefore fulfilled the requirements of the ISO protocol. In the multivariate analysis with the linear mixed model, the difference was associated with the cuff size for SBP and pulse pressure for DBP. The Omron HEM-7080IC passed the ISO requirements for oldest-old individuals aged 85 years or older. This device can be recommended for clinical and self/home use in oldest-old populations.


SUMOylation of insulin-like growth factor 1 receptor, promotes proliferation in acute myeloid leukemia.
Current valid treatments for acute myeloid leukemia (AML) include chemotherapy and hematopoietic stem cell transplantation, which are defective and limited respectively. The insulin-like growth factor 1 receptor (IGF-1R) is up-regulated in many solid tumors; therefore, it may be a target for tumor therapy. Interestingly, IGF-1R is modified by SUMOylation, a type of reversible post-translational modification. In this study, we found that IGF-1R was increased in both cell lines and clinical samples of AML and was modified by SUMO-1. Furthermore, IGF-1, ligand of IGF-1R, induced the up-regulation of IGF-1R and increased the proliferation of leukemia cell line. After mutation of Lys(1025) and Lys(1100) in IGF-1R, the evolutionarily conserved lysine residues were identified as the SUMOylation sites of IGF-1R, because the SUMOylation of IGF-1R in these mutants was significantly inhibited. Furthermore, the cell proliferation mediated by IGF-1 was also reduced. After inhibition of UBC9, the activating enzyme of SUMOylation, co-expression of IGF-1R and SUMO-1 was down-regulated, and cell proliferation was also inhibited. However, cell apoptosis was not significantly affected. These results suggest that IGF-1R and its SUMOylation may be a new therapeutic target for strategy of AML.


Whisker electromyograms signify awake and anesthetized states in mice.
The behavioral state of animals is essential information for functional recordings of neuronal activity; practically, the exact timing when animals recover from anesthesia is important information. Recordings of cortical local field potentials and dorsal neck electromyograms (EMGs), a widely used method to identify behavioral states, requires at least two recording electrodes, one of which also requires a craniotomy procedure. In the present study, recordings of whisker EMGs alone are sufficient to detect the state switch from anesthesia to awakening in head-fixed mice. This method uses a single electrode and thus is technically simple and demands a less physical burden to animals. Moreover, whisker EMGs recorded under anesthesia reflect respiratory rhythms.


What can phylodynamics bring to animal health research?
Infectious diseases are a major burden to global economies, and public and animal health. To date, quantifying the spread of infectious diseases to inform policy making has traditionally relied on epidemiological data collected during epidemics. However, interest has grown in recent phylodynamic techniques to infer pathogen transmission dynamics from genetic data. Here, we provide examples of where this new discipline has enhanced disease management in public health and illustrate how it could be further applied in animal health. In particular, we describe how phylodynamics can address fundamental epidemiological questions, such as inferring key transmission parameters in animal populations and quantifying spillover events at the wildlife-livestock interface, and generate important insights for the design of more effective control strategies.


The immunoglobulin hinge (interdomain) region.
The hinge region is a flexible amino acid stretch in the central part of the heavy chains of the IgG and IgA immunoglobulin classes, which links these 2 chains by disulfide bonds. It is rich in cysteine and proline amino acids, extremely variable in amino acid sequence, and has no resemblance to any other immunoglobulin region. The hinges in these 2 classes are compared and contrasted. Such a distinct molecular structure does not exist around the inter-heavy disulfide bonds of the other Ig classes, but a portion of the IgM heavy chain has similar properties to the gamma hinge. This similarity suggests one hypothesis for the genetic origin of the hinge region; data supporting 2 other hypotheses are also presented.


Remarkably variable reaction modes of frustrated Lewis pairs with non-conjugated terminal diacetylenes.
The frustrated Lewis pair P(o-tolyl)(3)/B(C(6)F(5))(3) reacts with 1,7-octadiyne by acetylene C-C coupling to yield the zwitterionic product 2a. In contrast, the P(o-tolyl)(3)/B(C(6)F(5))(3) Lewis pair reacts with 1,6-heptadiyne by a sequence involving 1,1-carboboration of a terminal acetylene to eventually yield the heterocyclic product 4.


Neuropsychological abilities of children with epilepsy.
One hundred eighteen epileptic children, aged 6-15 years, underwent detailed neuropsychological testing including the Wechsler Intelligence Scale for Children-Revised and the age-appropriate Halstead-Reitan battery. Eight had classical absence seizures only, eight had classic absence seizures and generalized tonic-clonic seizures, 30 had generalized tonic-clonic seizures only, 31 had partial seizures only, 20 had partial seizures and generalized seizures, 15 had atypical absence seizures, and five had minor motor seizures. A control group of 100 children without seizures, matched to the general population for intelligence and matched to the seizure cases for age, underwent identical testing. The Wechsler full-scale intelligence quotient (FSIQ) of cases was significantly (p = 0.01) lower than that of controls and was related to seizure type. Children with minor motor or atypical absence seizures had the lowest average FSIQ (70 and 74, respectively). All seizure types were associated with below-control intelligence except classic absence only. Intelligence was also correlated with degree of seizure control. A highly significant inverse correlation between years with seizures and intelligence was found (p less than 0.0001). A rating of neuropsychological impairment, derived from all measures of brain function, was assigned to each child. Epileptic children had significantly more impairment than controls (p less than 0.0001). Children with seizures had been placed in special education or had repeated a grade in school almost twice as frequently as controls (p less than 0.001). Even though often placed in a class of younger children, their academic achievement was behind grade placement more often than in controls.(ABSTRACT TRUNCATED AT 250 WORDS)


Transmembrane helix orientation and dynamics: insights from ensemble dynamics with solid-state NMR observables.
As the major component of membrane proteins, transmembrane helices embedded in anisotropic bilayer environments adopt preferential orientations that are characteristic or related to their functional states. Recent developments in solid-state nuclear magnetic resonance (SSNMR) spectroscopy have made it possible to measure NMR observables that can be used to determine such orientations in a native bilayer environment. A quasistatic single conformer model is frequently used to interpret the SSNMR observables, but important motional information can be missing or misinterpreted in the model. In this work, we have investigated the orientation of the single-pass transmembrane domain of viral protein "u" (VpuTM) from HIV-1 by determining an ensemble of structures using multiple conformer models based on the SSNMR ensemble dynamics technique. The resulting structure ensemble shows significantly larger orientational fluctuations while the ensemble-averaged orientation is compatible with the orientation based on the quasistatic model. This observation is further corroborated by comparison with the VpuTM orientation from comparative molecular dynamics simulations in explicit bilayer membranes. SSNMR ensemble dynamics not only reveals the importance of transmembrane helix dynamics in interpretation of SSNMR observables, but also provides a means to simultaneously extract both transmembrane helix orientation and dynamics information from the SSNMR measurements.


Intraindividual and Interindividual Differences in Spontaneous Eye Blinking: Relationships to Working Memory Performance and Frontal EEG Asymmetry.
The rate and timing of spontaneous eye blinking (SB) may be used to explore mechanisms of cognitive activity in infancy. In particular, SB rate is believed to reflect some dimensions of dopamine function; therefore, we hypothesized that SB rate would relate to working memory performance and to frontal electroencephalogram (EEG) asymmetry. Forty, 10-mo-old infants completed an A-not-B task while SB and EEG were measured throughout. We found that SB rate varied across phases of the task, variability in SB rate was positively related to working memory performance, and frontal EEG asymmetry was related to individual differences in the rate of SB. Results provide indirect, but convergent support for the hypothesis that SB rate reflects dopamine function early in human development. As such, these results have implications for understanding the tonic and phasic effects of dopamine on cognitive activity early in human development.


Iontophoretic application of opiates to the locus coeruleus.
The vast majority of morphine-sensitive single units in the area examined were localized to the locus coeruleus. This corresponds well with the known distribution of the highest densities of opiate receptor sites in this region of the midbrain. The effect of iontophoretically applied morphine was a marked and prolonged depression of spontaneous activity. Levorphanol, an opiate agonist, produced an effect similar to that of morphine while comparable doses of dextrorphan, it's clinically inactive stereoisomer, did not. Naloxone and levallorphan prevented as well as reversed the depression due to application of agonists. While the units were depressed following the application of opiate agonists, the cells were still excited by the neurotransmitter acetylcholine. We conclude that (1) neuronal sensitivity to opiates has a high positive correlation with autoradiographically determined opiate receptor sites, and (2) this sensitivity to opiates is blocked by opiate antagonists and is stereospecific in nature.


Nosocomial bacteremia. An epidemiologic overview.
Each year nosocomial bacteremia develops in approximately 194,000 patients in U.S. hospitals (5/1,000); 75,000 die. These infections portend $.28 to $.86 billion added costs to health care. Most nosocomial bacteremias occur endemically and are secondary bacteremias, caused by postoperative wound or intra-abdominal infections, urinary tract infections or pneumonia; primary bacteremias most frequently originate from intravascular devices, but the source is unrecognized. Between 1965 and 1978, 97 epidemics of nosocomial bacteremia, including 11 of "pseudobacteremia," were reported. In contrast to endemic bacteremias, 78 percent of the epidemics involved primary bacteremias: 33 outbreaks stemmed from infusion therapy in some form, including seven epidemics traced to a contaminated commercial product. Two thirds of endemic nosocomial bacteremias and 79 percent of epidemics are caused by aerobic gram-negative bacilli. Pseudomonas cepacia, Pseudomonas maltophilia, Flavobacterium and Enterobacter agglomerans rarely cause endemic bacteremia and when encountered often signal an epidemic. Whereas predisposing host conditions greatly increase the risk of bacteremia endemically nosocomial epidemics occur mainly in immunocompetent patients and are related to what therapeutic measures have been taken: segregation in a special care unit (58 percent of outbreaks) or exposure to infusion therapy or other invasive procedures involving the bloodstream (65 percent). At present only about one fourth of endemic nosocomial bacteremias are in theory preventable by more consistent application of existent knowledge of asepsis. The potential for prevention seems greatest for epidemic bacteremias, most of which are related to exposure to invasive devices, to a common source of contamination, or both.


Fluorescence Microscopy: A Field Guide for Biologists.
Optical microscopy is a tool for observing objects, and features within objects, that are not visible to the unaided eye. In the life sciences, fluorescence microscopy has been widely adopted because it allows us to selectively observe molecules, organelles, and cells at multiple levels of organization. Fluorescence microscopy encompasses numerous techniques and applications that share a specialized technical language and concepts that can create barriers for researchers who are new to this area. Our goal is to meet the needs of researchers new to fluorescence microscopy, by introducing the essential concepts and mindset required to navigate and apply this powerful technology to the laboratory.