Morphology-tuned fabrication of highly transparent and flexible nanostructures at room temperature.
Shape controlled fabrication of highly transparent and flexible nanostructures (nanocone, nanoneedle, nanowalls) onto nafion substrate were performed at room temperature by simple ion irradiation method. By varying the ion incidence angle and irradiated ion, the surface morphology and alignment were gradually changed from nanocone to nanowall pattern. Interestingly, ion irradiation onto the nafion surface led to the systematic pattern without surface modification by external addition of any material onto the substrate prior to ion irradiation. The antireflective performance of the nanostructures made the surface more transparent compared to the bare substrate. The growth mechanism of the nanostructures arrays with different shapes is also discussed briefly. This straightforward and fast method is thought to be very enticing for surface engineering and fabrication of antireflective nanostructures of controlled dimension onto different kinds of plastic substrates. These kinds of transparent nanostructures might have a remarkable role for promising commercial impact in wide variety of areas such as dust-free devices, see-through devices, nanofluidics, and drug delivery.


Orbital and Ocular Ischemic Syndrome With Blindness After Facial Filler Injection.
The authors herein describe a case of orbital and ocular ischemic syndrome with blindness after cosmetic hyaluronic acid filler injection. Orbital function, but not visual function, returned after treatment with orbital hyaluronidase and corticosteroids.


Binding site alteration is responsible for field-isolated resistance to Bacillus thuringiensis Cry2A insecticidal proteins in two Helicoverpa species.
Evolution of resistance by target pests is the main threat to the long-term efficacy of crops expressing Bacillus thuringiensis (Bt) insecticidal proteins. Cry2 proteins play a pivotal role in current Bt spray formulations and transgenic crops and they complement Cry1A proteins because of their different mode of action. Their presence is critical in the control of those lepidopteran species, such as Helicoverpa spp., which are not highly susceptible to Cry1A proteins. In Australia, a transgenic variety of cotton expressing Cry1Ac and Cry2Ab (Bollgard II) comprises at least 80% of the total cotton area. Prior to the widespread adoption of Bollgard II, the frequency of alleles conferring resistance to Cry2Ab in field populations of Helicoverpa armigera and Helicoverpa punctigera was significantly higher than anticipated. Colonies established from survivors of F(2) screens against Cry2Ab are highly resistant to this toxin, but susceptible to Cry1Ac. Bioassays performed with surface-treated artificial diet on neonates of H. armigera and H. punctigera showed that Cry2Ab resistant insects were cross-resistant to Cry2Ae while susceptible to Cry1Ab. Binding analyses with (125)I-labeled Cry2Ab were performed with brush border membrane vesicles from midguts of Cry2Ab susceptible and resistant insects. The results of the binding analyses correlated with bioassay data and demonstrated that resistant insects exhibited greatly reduced binding of Cry2Ab toxin to midgut receptors, whereas no change in (125)I-labeled-Cry1Ac binding was detected. As previously demonstrated for H. armigera, Cry2Ab binding sites in H. punctigera were shown to be shared by Cry2Ae, which explains why an alteration of the shared binding site would lead to cross-resistance between the two Cry2A toxins. This is the first time that a mechanism of resistance to the Cry2 class of insecticidal proteins has been reported. Because we found the same mechanism of resistance in multiple strains representing several field populations, we conclude that target site alteration is the most likely means that field populations evolve resistance to Cry2 proteins in Helicoverpa spp. Our work also confirms the presence in the insect midgut of specific binding sites for this class of proteins. Characterizing the Cry2 receptors and their mutations that enable resistance could lead to the development of molecular tools to monitor resistance in the field.


Immune Checkpoint Inhibitor Therapy: What Line of Therapy and How to Choose?
Immunotherapy is now an established part of the treatment paradigm for advanced non-small cell lung cancer (NSCLC), but the line of therapy and the sequence of agents are still in flux. In this time when much is to be learned, the optimal therapy for most patients in both the first-line and previously treated settings is in the context of a clinical trial. For standard therapy, however, there are good data to support the practice of programmed death-ligand 1 (PD-L1) testing in the front-line advanced setting and to use pembrolizumab as first-line therapy for those with ≥50% PD-L1 expression. In those who have progressed after receiving platinum-based chemotherapy in the first-line, multiple PD-1/PD-L1 agents are available and currently approved, including nivolumab, pembrolizumab, and atezolizumab. There are no data to suggest that one agent is more efficacious than the others, but pembrolizumab should be reserved for patients with PD-L1 expression ≥1%. Prescribers and patients must be cognizant of the toxicity profile of these agents, as severe immune-related adverse events can occur with therapy. At this time, this practice pattern for immunotherapy in the first- and second-line can be considered the standard of care, but new data are likely to impact the role of immunotherapy as monotherapy or in combination in the near future.


Providing protection for doctors.
Over the last decade the number of negligence cases brought against doctors, dentists and other healthcare professional has increased significantly in many countries around the world. In addition, the proliferation of the pathways of accountability in many countries means that doctors are feeling undervalued and vulnerable and are therefore seeking assistance and protection more than ever. The effect of a claim or complaint on a doctor can be devastating both personally and professionally. The relationship with the patient is damaged and an increase in defensive practice ultimately causes an increase in healthcare costs. Patient expectations have increased. Patients are more knowledgeable than they were five years ago and the demands on the professions are increasing daily. Unfortunately because of the long delays that are seen between an incident and a claim it is very difficult to predict what reserves are required in the future. We have seen a number of organisations pull out of the business over the last year and it highlights the importance of having an understanding of the needs of the professions and the ability to track trends in litigation in order to set appropriate subscription rates. Doctors and other healthcare professionals require more than just financial protection. They need support from their colleagues and assistance from experienced lawyers in order to help restore their confidence and ensure that they can continue to practice for the benefit of their patients in the future.


Demystifying Nursing Theory: A Christian Nursing Perspective.
How does nursing theory apply to nursing practice? Nursing theory can explain the why and how of nursing practice, guide nursing interventions, and provide a framework for measuring outcomes. This article briefly explains nursing theory, provides examples for applying theory to nursing practice, and proposes questions for examining the consistency of nursing theories with Christian perspectives. A helpful table illustrating grand, middle-range, and situation-specific theories and their application to nursing practice and research, along with references, is provided online as supplemental digital content. Three caring theories are analyzed from biblical beliefs.


Sentinel Lymph Node Biopsy: Evolution of the Technique Since the Original Description by Morton et al. in 1992.
Donald Morton was a truly amazing man: a remarkable scientist and an outstanding, inspirational surgical oncologist. For those of us who had the great fortune to know him personally, it was an experience that we will always remember with warmth and gratitude. Hundreds of thousands, possibly millions, of patients in the future will also be grateful to him when they benefit from his original but simple idea that has so dramatically improved the surgical approach to patients with cancers that may metastasize to regional lymph nodes: the sentinel lymph node biopsy concept.


Inhibition of Necroptosis Rescues SAH-Induced Synaptic Impairments in Hippocampus via CREB-BDNF Pathway.
Subarachnoid hemorrhage (SAH) is a devastating form of stroke that leads to incurable outcomes. Increasing evidence has proved that early brain injury (EBI) contributes mostly to unfavorable outcomes after SAH. A previously unknown mechanism of regulated cell death known as necroptosis has recently been reported. Necrostatin-1 (nec-1), a specific and potent inhibitor of necroptosis, can attenuate brain impairments after SAH. However, the effect of nec-1 on the hippocampus and its neuroprotective impact on synapses after SAH is not well understood. Our present study was designed to investigate the potential effects of nec-1 administration on synapses and its relevant signal pathway in EBI after SAH. Nec-1 was administrated in a rat model via intracerebroventricular injection after SAH. Neurobehavior scores and brain edema were detected at 24 h after SAH occurred. The expression of the receptor-interacting proteins 1 and 3 (RIP1and3) was examined as a marker of necroptosis. We used hematoxylin and eosin staining, Nissl staining, silver staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) to observe the morphological changes in hippocampus. The protective effect of nec-1 on synapses was evaluated using western blotting and electron microscopy and Western blotting was used to detect the cAMP responsive element binding (CREB) protein and brain-derived neurotrophic factor (BDNF), and we used transmission electron microscopy and TUNEL to detect the protective effects of nec-1 when a specific inhibitor of CREB, known as 666-15, was used. Our results showed that in the SAH group, RIP1, and RIP3 significantly increased in the hippocampus. Additionally, injection of nec-1 alleviated brain edema and improved neurobehavior scores, compared with those in the SAH group. The damage to neurons was attenuated, and synaptic structure also improved in the Sham+nec-1 group. Furthermore, nec-1 treatment significantly enhanced the levels of phospho-CREB and BDNF compared with those in the SAH group. The protective effect of nec-1 could hindered by 666-15. Thus, nec-1 mitigated SAH-induced synaptic impairments in the hippocampus through the inhibition of necroptosis in connection with the CREB-BDNF pathway. This study may provide a new strategy for SAH patients in clinical practice.


[Mechanism of molecular backgrounds of osteoarthritis].
In efforts to know the molecular backgrounds underlying the osteoarthritis (OA) development, examinations using the experimental mouse models confirmed that type X collagen (COL10A1) that is characteristic of chondrocyte hypertrophy and initiates endochondral ossification was strongly expressed in the OA cartilage. Recent COL10A1 gene transcription assay and mouse genetic approaches found that endochondral ossification signals like hypoxia-inducible factor 2α (HIF-2α), Runx2, C/EBPβ, carminerin, syndecan-4, hedgehog, and Notch signaling are involved in the OA development. The endochondral ossification process is likely to cause osteophyte formation at the periphery cartilage of the joint and degradation at the center during OA progression. Molecules related to endochondral ossification might become therapeutic targets altering the course of this disabling disease.


Serum Trace Elements Profile in Graves' Disease Patients with or without Orbitopathy in Northeast China.
The purpose of the present study was to investigate serum trace elements in Graves' disease (GD) patients with or without orbitopathy in Northeast China. Patients with newly diagnosed Graves' disease (HyGD) (n = 66), GD patients with euthyroid status or subclinical thyroidism after treatment (EUGD) (n = 55), GO patients with euthyroid status or subclinical thyroidism after treatment (GO) (n = 57), and normal controls (NC) (n = 66) were enrolled in this study. Serum trace elements were measured with ICP-MS. Serum selenium (Se) levels in EUGD group (median: 7.53 µg/dL), HyGD group (median: 6.76 µg/dL), and GO group (median: 7.40 µg/dL) were significantly lower than those in NC group (median: 9.20 µg/dL, all P < 0.01). Serum copper (Cu) levels in GO group (median: 95.93 µg/dL) were significantly lower than those in the NC group (median: 113.59 µg/dL, P = 0.015). After being adjusted for multivariables, thyroid-specific antibodies grade was associated with low Se levels. Hyperthyroidism and thyroid-specific antibodies grade were associated with high Cu levels. In addition, orbitopathy was associated with low Cu levels. Thyroid autoimmunity was associated with low Se levels. Hyperthyroidism and thyroid autoimmunity may be associated with relatively high serum Cu levels. Alternatively, ophthalmopathy may be related to low serum Cu levels.


Comparison between Bilateral and Unilateral Sudden Sensorineural Hearing Loss.
Bilateral sudden sensorineural hearing loss (BSSHL) is rare and assumed to be a different clinical entity compared to unilateral SSHL (USSHL). This study examined the differences between the idiopathic BSSHL and USSHL. Forty-six sequential BSSHL patients (Se-BSSHL) and 68 simultaneous BSSHL (Si-BSSHL) were consecutively admitted between June 2008 and December 2015. Two sets of patients served as control groups: (1) USSHL patients with healthy contralateral ear and (2) USSHL patients with contralateral preexisting hearing loss (USSHLwCHL). We retrospectively analyzed differences among four cohorts using analysis of variance, Kruskal-Wallis test, Welch's t-test, and Chi-square test as appropriate before and after propensity score matching (PSM) based on age, gender, and body mass index (BMI). The prevalence of idiopathic BSSHL was 8.6% (114/1329) among the total SSHL patients. In the total cohort, USSHL patients tended to be younger, female, and tended to have lower BMI, renal parameters, and total cholesterol in addition to higher high-density lipoprotein compared to the other three groups. Most routine blood indicators, some coagulation markers, and immunoglobulin M (H = 13.4, P = 0.004) were significantly different among the study groups. After PSM, the major significant differences were found in audiometric characteristics. Si-BSSHL and Se-BSSHL patients demonstrated similar hearing thresholds as USSHL but were significantly better than the USSHLwCHL patients across most frequencies before and after treatment (H = 30.0, P < 0.001 for initial hearing and H = 12.0, P = 0.007 for final hearing). Moreover, the BSSHL patients showed different hearing loss distribution patterns (more descending type, χ2 = 33.8, P = 0.001) with less hearing gain (H = 17.5, P < 0.001) compared to the USSHL patients. Idiopathic BSSHL is a relatively rare subtype of SSHL with a higher rate of descending audiogram type and inferior hearing outcome rather than being classified as a completely different disease entity compared to USSHL.


Pseudogestational sac in ectopic pregnancy.
A case of tubal pregnancy demonstrated by sonography is presented. In addition to the true ectopic gestational sac, an intra-uterine structure closely resembling a gestational sac was detected simultaneously. Such a finding of a pseudogestational sac in the uterine cavity may mislead to the diagnosis of an intra-uterine gestation. Thus, this sonographic finding is not sufficient to exclude the diagnosis of ectopic pregnancy. Clinicians should be aware of the possible finding of a pseudogestational sac in cases of ectopic pregnancy and the pathophysiological basis of this phenomenon is discussed.


In vivo actions of clozapine and haloperidol on the turnover rate of acetylcholine in rat striatum.
We have measured acetylcholine (ACh) content and turnover rate (TRACh) in striatum and cortex of rats receiving haloperidol and clozapine i.p. Both clozapine (30 mumol/kg) and haloperidol (10 mumol/kg) reverse the decrease in striatal TRACh elicited by apomorphine (11 mumol/kg) while each antipsychotic affects the steady state and the TRACh in striatum differently. Haloperidol fails to change striatal ACh content but increases the TRACh; chozapine (15 and 30 mumol/kg) neither decreases the content of ACh nor changes the TRACh in striatum. Moreover, 60 or 90 mumol/kg of clozapine causes a 40% decrease in ACh content without affecting the TRACh. Clozapine, but not haloperidol, antagonizes the increase in ACh content and the decrease in TRACh elicited by arecoline (64 mumol/kg) and oxotremorine (9 mumol/kg) in striatum. Clozapine resembles trihexylphenidyl (14 mumol/kg) and benztropine (12 mumol/kg) because it decreases the ACh content of striatum without changing the TRACh. Moreover, clozapine and benztropine reverse the increase in striatal TRACh elicited by haloperidol. The increase in striatal TRACh elicited by haloperidol could be of value to explain the extrapyramidal action of this drug. The anticholinergic action of clozapine could explain the absence of extrapyramidal side effects observed with this drug.


Production of laccase as the sole phenoloxidase by a Brazilian strain of Pleurotus pulmonarius in solid state fermentation.
The production of laccase by a Brazilian strain of Pleurotus pulmonarius was studied in solid state fermentation using wheat bran as substrate. Among oxidative and hydrolytic enzymes tested (laccase, aryl alcohol oxidase, lignin peroxidase, Mn peroxidase, xylanase and cellulase), laccase was the main enzyme produced by P. pulmonarius. The most suitable condition for maximum production of laccase (8,600 U/g substrate) was initial moisture content of 75% and 5 days of cultivation at 30 degrees C. The optimum pH and temperature for laccase activity were found to be 6.5 and 50 degrees C, respectively. P. pulmonarius laccase was stable at 50 degrees C for more than 6 hours, and it retained about 73% and 18% of its activity when heated for 1 h at 55 and 60 degrees C, respectively. The enzyme was greatly stable at alkaline pH, but not at acidic pH. The laccase activity appear to be correlated with the ability of crude extract to decolourize several industrial dyes.


The new combination of risk factors determining a high risk of gestational diabetes mellitus.
The aim of this study was to identify early markers of gestational diabetes mellitus (GDM) and to reveal the most significant of them. A total of 548 pregnant women were screened for GDM between weeks 24 and 28 of gestation, as defined by International Association of Diabetes In Pregnancy Study Groups (IADPSG) criteria, in a retrospective case-control study. First trimester maternal fasting glucose, anthropometric parameters and blood pressure were obtained from medical records. Classification Tree Method was used to identify combination of early pregnancy risk factors that predict the highest risk of the development of GDM in later pregnancy. The combination of Body Mass Index (BMI) >38.6 kg/m² with, abdominal circumference >91.5 cm and fasting glucose >4.5 mmol/L was associated with a 13-fold increased risk of GDM as compared to women who do not have this combination of symptoms (OR 13.2 95% CI: 2.7-63.3, P<0.001). In women with BMI less than 38,6 kg/m ² the combination of fasting glucose >4.5 mmol/L, abdominal circumference >91.5 cm with the presence of polycystic ovary syndrome (PCOS) was associated with a 6-fold increased risk of GDM as compared with women who do not have this combination of symptoms (OR=7.6, 95% CI: 1.9-30.02, P=0.003). A higher BMI, abdominal circumference, fasting glycemia in the first trimester of pregnancy and the presence of PCOS predict increased GDM risk. Taking these combinations into consideration may facilitate identification of women at particular risk for GDM.


Comprehensive functional screening of miRNAs involved in fat cell insulin sensitivity among women.
The key pathological link between obesity and type 2 diabetes is insulin resistance, but the molecular mechanisms are not entirely identified. micro-RNAs (miRNA) are dysregulated in obesity and may contribute to insulin resistance. Our objective was to detect and functionally investigate miRNAs linked to insulin sensitivity in human subcutaneous white adipose tissue (scWAT). Subjects were selected based on the insulin-stimulated lipogenesis response of subcutaneous adipocytes. Global miRNA profiling was performed in abdominal scWAT of 18 obese insulin-resistance (OIR), 21 obese insulin-sensitive (OIS), and 9 lean women. miRNAs demonstrating differential expression between OIR and OIS women were overexpressed in human in vitro-differentiated adipocytes followed by assessment of lipogenesis and identification of miRNA targets by measuring mRNA/protein expression and 3'-untranslated region analysis. Eleven miRNAs displayed differential expression between OIR and OIS states. Overexpression of miR-143-3p and miR-652-3p increased insulin-stimulated lipogenesis in human in vitro differentiated adipocytes and directly or indirectly affected several genes/proteins involved in insulin signaling at transcriptional or posttranscriptional levels. Adipose expression of miR-143-3p and miR-652-3p was positively associated with insulin-stimulated lipogenesis in scWAT independent of body mass index. In conclusion, miR-143-3p and miR-652-3p are linked to scWAT insulin resistance independent of obesity and influence insulin-stimulated lipogenesis by interacting at different steps with insulin-signaling pathways.


Organizational Structure Change and Hybridity: Enhancing Uncertainty as a Response to Competing and Changing Institutional Logics.
Confronting the uncertain environment, this article adopts a case research approach to resonate with the studies of hybridity. It aims to explain how the perception of uncertainty in the institutional environment affects the adaptation of organizational structure in pursuing legitimacy for hybrid organizations. Based on the empirical data collected from a two-staged fieldwork and in-depth interviews, the case analysis concentrates on the correlation between the evolution of institutional logics and organizational structure change from a diachronic perspective. The findings indicate that in the face of competing and changing institutional logics, Chinese mass media organizations have gradually shifted from a dominated blending strategy in the exploration stage to a deeply compartmentalizing strategy in the stable stage. The hybrids can deal with the uncertainty of the institutional environment by enhancing the uncertainty of the organizational structure. Consequently, the case evolves an organizational integration through internal legitimacy. It manifests a possibility for hybrids of combining the two major response mechanisms in one process.


Segmental distraction of the midface in a patient with Crouzon syndrome.
We treated midface hypoplasia in a 20-year-old woman with Crouzon syndrome using a rigid external distraction device. The patient showed severe exophthalmos and maxillary retrusion, although relatively good occlusion had been achieved by long-term orthodontic procedures. We considered that our patient's particular condition could not be resolved by the usual Le Fort III osteotomy/midface distraction procedure, so we devised a segmental approach. The midface, mobilized by Le Fort III osteotomy, was divided into two segments by Le Fort I osteotomy; each fragment was connected to the rigid external distraction device to be distracted separately. Distraction was begun after 1 day at 1 mm/day. The upper and lower segments were distracted over 17 and 12 days, respectively. The patient's occlusion was fully corrected, and her facial contour was significantly improved. After 3 weeks of consolidation, we removed the distraction device. The clinical course was without complication, and no relapse was observed on the cephalogram or computed tomography scan obtained 1 year after the procedure. Our modified technique was helpful in increasing the usefulness of the external distraction system and in refining the midface distraction procedure.


Acromelia-oligodontia syndrome.
This case report describes a patient with ankyloglossia, oligodontia, unilateral hypoplasia of the zygoma and mandible, along with bilateral distal reduction anomalies of his limbs without long bone abnormalities. This may represent a mild variant of oromandibular limb hypogenesis syndrome, expanding the phenotypic spectrum, or a previously unrecognized malformation syndrome.


Early physiological consequences of fire as an abiotic stressor in metabolic source and sink of young Brutian pine (Pinus brutia Ten.).
Climatic change causes gradual deforestation, partly through forest fires. However, fire has not been seen as an oxidative stressor on surviving forest trees. In addition, discrimination of stress-induced responses from acclimation steps cannot be examined under prolonged stress. Thus, four young Brutian pine (Pinus brutia Ten.) trees, a fire-related species, were subjected to a simulation of a crown-fire event to evaluate its impact on the availability of soluble carbon (C) and nitrogen (N) and the redox status near fire-afflicted tissue. Total soluble sugars, amino acids and non-structural (NS) proteins in needles and phloem, the antioxidant ascorbic acid (AsA) and reactive oxygen species (ROS) in needles were investigated together with the phloem transport velocity. To examine the temporal progress of these parameters, samples were obtained prior to fire (pre-fire), 2 h after fire, the following day (Day 1) and the following week (Week 1). Findings were categorized into shock reactions (2 h) and acclimation steps. Phloem transport accelerated 2 h postfire by almost 30% and correlated negatively to phloem sugars. At the same time the phloem ratio of sugars/amino acids correlated negatively to needle ROS. The trees' main response at 2 h and particularly on Day 1 was a massive increase in phloem NS proteins. The acclimation process involved also significant increases in needle NS proteins and AsA, as well as significant depletion of phloem amino acids by 65% by Week 1. The highest availability of soluble C and N was recorded on Day 1 in the phloem. Regression models explained significantly the variability of most soluble compounds postfire. Our findings suggest sink control over the source and an advanced role of phloem transport in defense processes.


Gut Microbiota and Predicted Metabolic Pathways in a Sample of Mexican Women Affected by Obesity and Obesity Plus Metabolic Syndrome.
Obesity is an excessive fat accumulation that could lead to complications like metabolic syndrome. There are reports on gut microbiota and metabolic syndrome in relation to dietary, host genetics, and other environmental factors; however, it is necessary to explore the role of the gut microbiota metabolic pathways in populations like Mexicans, where the prevalence of obesity and metabolic syndrome is high. This study identify alterations of the gut microbiota in a sample of healthy Mexican women (CO), women with obesity (OB), and women with obesity plus metabolic syndrome (OMS). We studied 67 women, characterizing their anthropometric and biochemical parameters along with their gut bacterial diversity by high-throughput DNA sequencing. Our results indicate that in OB or OMS women, Firmicutes was the most abundant bacterial phylum. We observed significant changes in abundances of bacteria belonging to the Ruminococcaceae, Lachnospiraceae, and Erysipelotrichaceae families and significant enrichment of gut bacteria from 16 different taxa that might explain the observed metabolic alterations between the groups. Finally, the predicted functional metagenome of the gut microbiota found in each category shows differences in metabolic pathways related to lipid metabolism. We demonstrate that Mexican women have a particular bacterial gut microbiota characteristic of each phenotype. There are bacteria that potentially explain the observed metabolic differences between the groups, and gut bacteria in OMS and OB conditions carry more genes of metabolic pathways implicated in lipid metabolism.


Identification of four murine cDNAs encoding putative protein kinases from primitive embryonic stem cells differentiated in vitro.
Protein kinases transduce signals from extracellular ligands in the hematopoietic and other systems through direct phosphorylation of tyrosine, serine, or threonine residues. Little is known about the ligands and receptors that are important in the earliest stages of development--i.e., stem cell self-renewal and lineage commitment. We have made use of the lineage differentiation potential of the murine embryonic stem cell system to clone partial cDNAs encoding four putative protein kinases. Three of the four genes contain the highly conserved residues Asp-Phe-Gly in domain VII of the protein kinase family. These genes are candidates for receptors or downstream effectors of cytokines that regulate self-renewal and lineage commitment in embryogenesis.


Coevolution drives the emergence of complex traits and promotes evolvability.
The evolution of complex organismal traits is obvious as a historical fact, but the underlying causes--including the role of natural selection--are contested. Gould argued that a random walk from a necessarily simple beginning would produce the appearance of increasing complexity over time. Others contend that selection, including coevolutionary arms races, can systematically push organisms toward more complex traits. Methodological challenges have largely precluded experimental tests of these hypotheses. Using the Avida platform for digital evolution, we show that coevolution of hosts and parasites greatly increases organismal complexity relative to that otherwise achieved. As parasites evolve to counter the rise of resistant hosts, parasite populations retain a genetic record of past coevolutionary states. As a consequence, hosts differentially escape by performing progressively more complex functions. We show that coevolution's unique feedback between host and parasite frequencies is a key process in the evolution of complexity. Strikingly, the hosts evolve genomes that are also more phenotypically evolvable, similar to the phenomenon of contingency loci observed in bacterial pathogens. Because coevolution is ubiquitous in nature, our results support a general model whereby antagonistic interactions and natural selection together favor both increased complexity and evolvability.


[Mild traumatic brain injury and its psychiatric assessment].
Mild traumatic brain injuries without circumscripted necrotic areas in brain tissue were called concussion in classic terminology. It was generally assumed, that such lesions were to heal without any residues. This notion can not be upheld completely any longer, since according to today's state of knowledge on the pathogenesis of brain trauma, chronic troubles and impairments may occur even after mild traumatic brain injuries. Besides, a number of psychosocial stress factors making it more difficult to cope with the posttraumatic disturbances and the new challenging life situation, play a marked role as to the outcome. In mild brain injuries, these environmental factors as well as a general lack of internal resources may be even more crucial than the trauma's severity by itself.


Influence of cigarette smoking on osteonecrosis of the femoral head (ONFH): a systematic review and meta-analysis.
Current studies demonstrate controversy regarding the relationship between cigarette smoking and osteonecrosis of the femoral head (ONFH). We conducted a meta-analysis to evaluate the association between smoking and ONFH. Relevant articles published before September 2016 were identified by a systematic search of EMBASE and MEDLINE via Ovid. Summary odds ratios (OR) were calculated using random effects models, and study quality was assessed using a modified Newcastle-Ottawa scale. 102 citations were screened and 7 case-control studies were identified and included in the review. When compared with nonsmokers, current smokers had a higher risk of developing ONFH (OR 2.53; 95% confidence interval [CI] 1.68-3.79), as did former smokers (OR 1.82; 95% CI, 1.10-3.00). Within the group of current smokers, those classified as heavy smokers (with a daily number >20 cigarettes/day) demonstrated higher risks of ONFH (OR 2.03; 95% CI, 1.29-3.19), and light smokers classified as smoking <20 cigarettes/day, also demonstrated a higher risk of ONFH when compared with nonsmokers (OR 1.73; 95% CI, 1.06-2.83). When smoking was classified by pack-years, heavy smokers (>20 pack-years) were at a higher risk of ONFH (OR 2.26; 95% CI, 1.24-4.13), but no significant difference in risk was identified in light smokers (<20 pack-years) (OR 1.81; 95% CI, 0.88-3.71) when compared with nonsmokers. Our meta-analysis showed that current smokers were at a higher risk of ONFH, this high risk can also be found in former smokers. And heavy cigarette smoking showed a higher risk of ONFH than light smoking.


Conversation Analysis of Clients' Active Resistance to Veterinarians' Proposals for Long-Term Dietary Change in Companion Animal Practice in Ontario, Canada.
The impact of nutrition on animal health requires effective diet-related treatment recommendations in veterinary medicine. Despite low reported rates of veterinary clients' adherence with dietary recommendations, little is known about how clients' resistance to nutritional proposals is managed in the talk of veterinary consultations. This conversation-analytic study investigated clients' active resistance to veterinarians' proposals for long-term changes to cats' and dogs' diets in 23 segments from 21 videotaped appointments in Ontario, Canada. Clients' accounts suggested the proposals themselves or nutritional modifications were unnecessary, inappropriate, or unfeasible, most often based on patients' food preferences, multi-pet feeding issues, current use of equivalent strategies, or current enactment of the proposed changes. Resistance arose when veterinarians constructed proposals without first gathering relevant diet- and patient-related information, soliciting clients' perspectives, or educating them about the benefits of recommended changes. Veterinarians subsequently accommodated clients' concerns more often when resistance involved patient- or client-related issues rather than clients' lack of medical knowledge. The design of subsequent proposals accepted by clients frequently replaced dietary changes in the initial proposals with nutritional or non-nutritional alternatives and oriented to uncertainty about adherence. This study provides evidence-based findings for developing effective communication training and practice guidelines in nutritional assessment and shared decision-making.


Novel single-source high-pitch protocol for CT angiography of the aorta: comparison to high-pitch dual-source protocol in the context of TAVI planning.
Purpose Computed tomography (CT) is increasingly being used for planning purposes prior to trans-arterial valve implantation (TAVI). High-pitch protocols using a 2nd generation dual-source CT (DSCT) allow for a comprehensive assessment of the aortic valve anulus, its distance to the coronary artery ostia, the aortic bulbus and the iliofemoral arteries with very low radiation exposure and low amount of contrast agent. The aim of this study was to evaluate the image quality of a comparable high-pitch scan mode in a modern single-source CT (SSCT) system. Methods 40 patients with severe symptomatic aortic valve stenosis have been examined for planning purposes prior to TAVI. The first 20 consecutive patients were examined with a 2nd generation DSCT system using a high-pitch scan mode (pitch value 3.4) and 60 ml of contrast agent. The second group of 20 consecutive patients were examined with a 128-slice SSCT system, using a high-pitch scan mode (pitch value of 1.7) and 60 ml of contrast agent. Image quality of the aortic valve, the ascending aorta, the coronary artery ostia, the iliofemoral arteries and overall image quality were graded in a blinded fashion using a 4-point-grading-scale. Furthermore, signal intensity and image noise were derived in the ascending aorta and in the ilio-femoral arteries. Results There was a minor but significant difference in the overall image quality score with lower image quality in SSCT (3.5 ± 0.6) when compared to DSCT (3.85 ± 0.4; p = 0.037). The mean image quality score was significantly higher in patients examined in DSCT when compared to SSCT regarding the evaluability of the coronary ostia (4.0 vs. 3.5; p < 0.01) and the image quality of the ascending aorta (4.0 vs. 3.5; p < 0.01). There was no significant difference in evaluation of the aortic valve and its anulus (3.85 for DSCT and 3.65 for SSCT; p = 0.149) and image quality of the iliofemoral arteries (3.65 for DSCT and 3.85 for SSCT; p = 0.140). Signal intensity and image noise did not differ significantly between both groups. Conclusions This study presents a novel high-pitch protocol for modern SSCT scanners, which allows CT angiography for TAVI planning with a similar radiation dose and contrast agent exposition and only small compromises in image quality compared to a high-pitch protocol on a DSCT scanner.


Exercise in the management of multiple sclerosis relapses: current evidence and future perspectives.
Relapses are a common feature of multiple sclerosis; however, recovery from relapses is often incomplete, with up to half of people experiencing residual disabilities postrelapse. Therefore, treatments are required to promote recovery of function and reduce the extent of residual disabilities postrelapse. Accordingly, this Perspective article explores the role of exercise in relapse management. Current evidence from two studies suggests that exercise in combination with steroid therapy improves disability and quality of life postrelapse, and may be more beneficial in promoting relapse recovery than steroid therapy alone. However, given the small number of studies and methodological limitations, further studies are required to understand the effects of exercise in relapse management and the mechanism through which exercise influences relapse recovery.


It's money that matters: the financial context of ethical decision-making in modern biomedicine.
While the importance of patient autonomy is widely acknowledged and discussed in the bioethics literature, clinicians' autonomy, their ability to make the best choices about patients' care free from outside interference, is far less debated. This paper takes one form of external influence over clinical decisions - the cost of drugs - and applies it to a specific case, that of HER2 positive breast cancer and the use of the drug Herceptin in the UK. Drawing on interviews with clinicians, researchers and policymakers, I explore the way financial decisions about Herceptin shape clinicians' autonomy, and how clinicians as individuals and as professional groups respond to these limits and seek to provide treatment to the highest number of the most deserving patients they can. The point of this paper is not to castigate bioethicists for misguidedly focusing on patient autonomy but point out that clinicians' autonomy may be so circumscribed by external factors that it may make no sense to speak of their actions as stemming from ethical decisions. At the same time, I suggest that financial constraints create areas at the margin of clinical practice which are deserving of bioethical consideration.


Purification, crystallization and preliminary X-ray studies of a p-nitrophenylphosphatase from Bacillus stearothermophilus.
Thermostable p-nitrophenylphosphatase from Bacillus stearothermophilus has been expressed in Escherichia coli, purified and crystallized. The crystals belong to space group C(2), with unit-cell parameters a = 67.17 A, b = 57.84 A, c = 62.49 A and alpha = 90.0 degrees, beta = 95.4 degrees, gamma = 90.0 degrees. Diffraction data were collected to 1.40 A resolution with a completeness of 94.7% (96.6% for the last shell), an R(fac) value of 0.074 (0.341) and an I/sigma (I) value of 30.1 (2.67).


A Feasibility Study of a Physical and Occupational Therapy-Led and Parent-Administered Program to Improve Parent Mental Health and Infant Development.
Extremely premature birth puts infants at high risk for developmental delay and results in parent anxiety and depression. The primary objective of this study was to characterize feasibility and acceptability of a therapist-led, parent-administered therapy and massage program designed to support parent mental health and infant development. A single cohort of 25 dyads - parents (24 mothers, 1 father) and extremely preterm (<28 wk gestation) infants - participated in the intervention. During hospitalization, parents attended weekly hands-on education sessions with a primary therapist. Parents received bi-weekly developmental support emails for 12 months post-discharge and were scheduled for 2 outpatient follow up visits. We collected measures of parent anxiety, depression, and competence at baseline, hospital discharge, and <4 and 12 months post-discharge. All feasibility targets were met or exceeded at baseline and discharge (≥70%). Dyads participated in an average of 11 therapy sessions (range, 5-20) during hospitalization. Lower rates of data collection adherence were observed over successive follow ups (range, 40-76%). Parent-rated feasibility and acceptability scores were high at all time points. Results support parent-rated feasibility and acceptability of the TEMPO intervention for extremely preterm infants and their parents in the Neonatal Intensive Care Unit.


Efficacy of photon-initiated photoacoustic streaming on apically extruded debris with different preparation systems in curved canals.
To determine the effect of photon-initiated photoacoustic streaming (PIPS) on the extrusion of debris using multiple-file (ProTaper Next-PTN) and single-file (One Shape-OS) continuous rotary systems in curved canals in human molar teeth. Sixty extracted maxillary first molar teeth with curved mesial roots, mature apices and of similar lengths were selected. Teeth having canals with apical diameters larger than size 15 were discarded. The teeth were randomly divided into four experimental groups (n = 15 teeth per group) according to the file used and irrigation systems: (i) OS with PIPS with a 2940 nm Er:YAG laser (0.3 W, 15 Hz, and 20 mJ), (ii) OS with conventional needle irrigation (CNI) with a 27-G needle, (iii) PTN with PIPS and (iv) PTN with CNI. The PIPS and CNI was applied during each file change for 20 s. Total irrigation and activation time was 1 min, and a total volume of 7.5 mL of bidistilled water was used as the irrigant. The apically extruded debris was collected into pre-weighed Eppendorf tubes. The tubes were then stored in an incubator at 70 °C for 5 days. The weight of dry extruded debris was assessed by subtracting the initial weight of the tube from the final weight. The results were analysed statistically using one-way analysis of variance and Tukey's post hoc tests. Bonferroni correction was used to compare the groups. The PIPS irrigation technique was associated with significantly more debris extrusion than the CNI system (P < 0.05). The single-file (One Shape-OS) rotary system was associated with more debris than the multiple-file (ProTaper Next-PTN) rotary systems when the same irrigation system was used (P > 0.05). The total amount of debris extruded apically by PIPS activation was significantly greater than that by CNI (P < 0.05). All file and irrigation systems extruded debris apically. PIPS activation was associated with significantly more extrusion debris in curved canals compared with no activation.


Presentations, Complications, and Challenges Encountered During Management of Type 1 Diabetes in Egyptian Children During COVID-19 Pandemic: A Single-Center Experience.
The coronavirus disease 2019 (COVID-19) pandemic has been associated with significant challenges pertaining to the management of children and adolescents with type 1 diabetes (T1D). Issues such as fear of infection and lockdown measures have resulted in delayed and more severe clinical presentations of this disease. This study aimed at reporting the frequency and severity of diabetic ketoacidosis (DKA) and the rate of DKA complications in children with diabetes who presented to the emergency unit during COVID-19 pandemic. Furthermore, the purpose of this study was to compare the data collected from the first and second COVID-19 waves with that of the pre-COVID-19 period and describe the challenges encountered during disease management. This cross-sectional study included all children and adolescents with T1D who presented to the emergency department at Abo El Rish Children's Hospital, Cairo University, during the first and second COVID-19 waves. It also included data collected from the pre-COVID-19 period. Demographic and clinical data, investigations, and management details were collected from the patients' medical records. Three hundred twenty-four Egyptian children and adolescents diagnosed with T1D were recruited. One hundred forty patients (43.2%) presented with severe DKA, and approximately 66% were newly diagnosed with T1D. The participants presented with manifestations suggestive of COVID-19, such as fever (29.5%), respiratory manifestations (7.2%), and gastrointestinal symptoms (14.7%). Thirty-seven patients were tested for severe acute respiratory syndrome coronavirus 2 infection using nasopharyngeal swabs, and four patients tested positive. Around 18% of patients developed hypokalemia during disease management. A comparison between these data and the data from previous years revealed that there was a significant increase in the number of newly diagnosed cases with more severe DKA at presentation and a higher frequency of development of hypokalemia during both COVID-19 waves. An increase in the frequency of newly diagnosed cases was identified during the first and the second COVID-19 waves compared with the pre-COVID-19 period. The patients presented with more severe DKA, probably due to a more delayed presentation. The frequency of hypokalemia development was also significantly higher, and the severity of DKA was associated with a longer ICU admission. Further studies are required to establish a definitive link between the COVID-19 pandemic and the severity of presentation.


Cefuroxime-induced acute renal failure.
Although drug-induced allergic nephritis (DIAN) is one of the most common problems seen by nephrologists, its true frequency is probably underestimated. Diagnosis is often difficult and is typically only made in patients without another explanation for deteriorating renal function, and is often based solely on improvement after drug withdrawal. The diagnosis may be made more difficult due to lack of typical allergic symptoms, presence of other drugs, or confounding factors and equivocal noninvasive laboratory studies. The gold standard for diagnosis is renal biopsy, but it is only rarely performed during the acute phase of the reaction and is not without risk. It is important to keep a high index of suspicion with regard to DIAN since it is usually rapidly reversible. Failure to recognize it and discontinue the offending agents may result in unnecessary morbidity and occasionally, irreversible renal failure. In our patient, DIAN possibly was related to cefuroxime, but the patient did not experience associated allergic symptoms. The diagnosis was supported by the temporal course of renal deterioration during exposure to cefuroxime and improvement on its discontinuation; the pattern repeated with rechallenge. This is the first reported case of suspected DIAN due to cefuroxime.


Inhibition of 5 alpha-reductase activity and alteration of nuclear testosterone. Dihydrotestosterone ratio in human genital skin fibroblasts.
17 beta-N, N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA) inhibits 5 alpha-reductase activity in cultured human genital skin fibroblasts. Enzyme kinetic studies analyzed by Eadie-Hofstee plots demonstrated that 4-MA is a competitive inhibitor, with an apparent Ki of 15 nM. 4-MA had a very low binding affinity for the androgen receptor. When fibroblasts were incubated in the presence of testosterone (T) and 4-MA, nuclear uptake of 5 alpha-dihydrotestosterone (DHT) decreased in parallel with the inhibition of 5 alpha-reductase activity. While the overall sum for the nuclear uptake of T and DHT diminished, the nuclear uptake of T increased. Biological androgen inactivity cannot be precluded on the basis of nuclear T plus DHT uptake.


Electron Compensation Effect Suppressed Silver Ion Release and Contributed Safety of Au@Ag Core-Shell Nanoparticles.
Silver nanoparticles (Ag NPs) have promising plasmonic properties, however, they are rarely used in biomedical applications because of their potent toxicity. Herein, an electron compensation effect from Au to Ag was applied to design safe Au@Ag core-shell NPs. The Ag shell thickness was precisely regulated to enable the most efficient electron enrichment in Ag shell of email@example.com NPs, preventing Ag oxidation and subsequent Ag+ ion release. X-ray photoelectron spectroscopy and X-ray absorption near-edge structure analysis revealed the electron transfer process from Au core to Ag shell, and inductively coupled plasma optical emission spectroscopy analysis confirmed the low Ag+ ion release from email@example.com NPs. Bare email@example.com NPs showed much lower toxicological responses than Ag NPs in BEAS-2B and Raw 264.7 cells and acute lung inflammation mouse models, and PEGylation of firstname.lastname@example.com NPs could further improve their safety to L02 and HEK293T cells as well as mice through intravenous injection. Further, diethylthiatri carbocyanine iodide attached firstname.lastname@example.com NPs exhibited intense surface-enhanced Raman scattering signals and were used for Raman imaging of MCF7 cells and Raman biosensing in MCF7 tumor-bearing mice. This electron compensation effect opens up new opportunity for broadening biomedical application of Ag-based NPs.


Simultaneous determination of allantoin, hypoxanthine, xanthine, and uric acid in serum/plasma by CE.
Allantoin (All) is an oxidative end product of purines in mammals. The small amount of All present in human plasma or serum results from free radical action on urate and may provide a stable marker of in vivo free radical activity. Because free radicals have been implicated in the development and progression of atherosclerosis, this study focused on the metabolic compounds of the All pathway. We propose a new fast CE (CE/UV) method for the simultaneous determination of All, uric acid (UA), hypoxanthine (HX), and xanthine (X) in human plasma. These products were quantified in the plasma of patients with chronic renal failure before hemodialysis (n = 6), patients with chronic heart failure (n = 6) and controls (n = 6). The filtered plasma were diluted ten-fold before the direct injection in CE/UV (195 nm), which allows separating the four compounds in less than 13 min. The metabolites were detectable at concentrations of 0.3-0.6 micromol/L. The method was linear over the range 0.5-150 micromol/L for All, HX, and X and 10-1500 micromol/L for UA (r > 0.99). The analytical performance of this method is satisfactory with intra-assay CV < 3.4%, inter-assay CV < 5% (HX and X < 7%), and recovery (93-101%). The proposed CE-UV method appears to be a useful tool for studying physiological and pathological changes of HX, UA, and All levels in plasma samples, the latter being a possible indicator of free radical damage in vivo.


Image Predictors of Treatment Outcome after Thoracic Aortic Dissection Repair.
Treatment of thoracic aortic dissection remains highly challenging and is rapidly evolving. Common classifications of thoracic aortic dissection include the Stanford classification (types A and B) and the DeBakey classification (types I to III), as well as a new supplementary classification geared toward endovascular decision making. By using various imaging techniques, the extent of the dissection, the location of the primary intimal tear, the shape of the aortic arch, and the zonal involvement of the aortic arch-factors that affect the treatment strategy-can easily be identified. Thoracic endovascular aortic repair (TEVAR) is generally performed in two groups of patients: (a) those with a surgically repaired type A dissection, and (b) those with a complicated type B dissection. Several imaging findings can help predict the course of remodeling of the dissected aorta after a repaired type A dissection and TEVAR. A spectrum of imaging findings exist with regard to favorable (positive) or failing (negative) remodeling. A schematic model with imaging support allows the classification of important causes of failing remodeling into proximal and distal groups, on the basis of the origin of the refilling of the false lumen and the underlying pathophysiology of pressurization. Refilling of the false lumen of the aorta after repair of a type A dissection is usually secondary to a persistent intimal tear at the aortic arch, a leak of the distal graft anastomosis, or refilling from the false lumen of a dissected aortic arch vessel. After TEVAR, false lumen refilling is most commonly due to an incomplete seal of the proximal landing related to the aortic tortuosity, an arch branch stump, a supra-arch chimney stent, or the TEVAR technique. Online supplemental material is available for this article. ©RSNA, 2018.


MR imaging and proton spectroscopy of neuronal injury in late-onset GM2 gangliosidosis.
Despite the ubiquity of G(M2) gangliosides accumulation in patients with late-onset G(M2) gangliosidosis (G(M2)G), the only clinical MR imaging-apparent brain abnormality is profound cerebellar atrophy. The goal of this study was to detect the presence and assess the extent of neuroaxonal injury in the normal-appearing gray and white matter (NAGM and NAWM) of these patients. During a single imaging session, 9 patients with late-onset G(M2)G and 8 age-matched normal volunteers underwent the following protocol: (1) T1- and T2-weighted and fluid-attenuated inversion recovery MR images, as well as (2) multivoxel proton MR spectroscopy (1H-MR spectroscopy) to quantify the distribution of the n-acetylaspartate (NAA), creatine (Cr), and choline (Cho), were obtained. The patients' NAA levels in the thalamus (6.5 +/- 1.9 mmol/L) and NAWM (5.8 +/- 2.1 mmol/L) were approximately 40% lower than the controls' (P = .003 and P = .005), whereas the Cr and Cho reductions ( approximately 30% and approximately 26%) did not reach significance (P values of .06-.1). All cerebellar metabolites, especially NAA and Cr, were much (30%-90%) lower in the patients, which reflects the atrophy. In late-onset G(M2)G, NAA decreases are detectable in NAGM and NAWM even absent morphologic (MR imaging) abnormalities. Because the accumulation of G(M2) gangliosides can be reduced pharmacologically, 1H-MR spectroscopy might be a sensitive and specific for detecting and quantifying neuroaxonal injury and monitoring response to emerging treatments.


The effect of music distraction on pain, anxiety and behavior in pediatric dental patients.
The purpose of this study was to determine if audio distraction could decrease patient anxiety, pain and disruptive behavior during pediatric dental procedures. Forty-five children between the ages of 4 to 6 years had two visits each involving restorative dentistry with local anesthesia in a mandibular quadrant. Visit #1 was a baseline session for all patients. During visit #2, the children were assigned to either an upbeat music group, a relaxing music group or a no music group. Variables measured were: (1) parent-reported anxiety via the Modified Corah Anxiety Scale, (2) self-reported anxiety via the Venham picture scale, (3) heart rate, (4) behavior via the North Carolina Behavior Rating Scale and (5) pain via a visual analogue scale. No significant differences were found among the three groups during experimental visit #2 across any variables. A majority of patients (90%) stated that they enjoyed the music and would like to listen to it during their next visit. Audio distraction was not an effective means of reducing anxiety, pain or uncooperative behavior during pediatric restorative dental procedures. However, patients did enjoy listening to the music during their visits.


Abdominal abscesses due to actinomycosis after laparoscopic cholecystectomy: case reports and review.
We describe 2 patients who presented to a health care facility with abdominal abscesses years after undergoing laparoscopic cholecystectomy that was complicated by gallstone spillage. In both patients, sample cultures yielded Actinomyces species and enteric organisms. In 1 patient, crystallographic analysis of abscess debris confirmed the presence of gallstones. Actinomyces species is a rare cause of abdominal abscesses that should be considered in this patient population.


Children's Developing Intuitions About the Truth Conditions and Implications of Novel Generics Versus Quantified Statements.
Generic statements express generalizations about categories and present a unique semantic profile that is distinct from quantified statements. This paper reports two studies examining the development of children's intuitions about the semantics of generics and how they differ from statements quantified by all, most, and some. Results reveal that, like adults, preschoolers (a) recognize that generics have flexible truth conditions and are capable of representing a wide range of prevalence levels; and (b) interpret novel generics as having near-universal prevalence implications. Results further show that by age 4, children are beginning to differentiate the meaning of generics and quantified statements; however, even 7- to 11-year-olds are not adultlike in their intuitions about the meaning of most-quantified statements. Overall, these studies suggest that by preschool, children interpret generics in much the same way that adults do; however, mastery of the semantics of quantified statements follows a more protracted course.


[Effect of effective components of Huanglian Jiedu decocting on NF-kappaB in cultured rat cerebral microvascular endothelial cells injury induced by hypoxia and reoxygenation].
To investigate the protective mechanism of geniposide, baicalin and berberine on hypoxia and reoxygenation injury in cultured rat cerebral microvascular endothelial cells. To establish a model of hypoxia four hours and reoxygenation twelve hours injury in rat cerebral microvascular endothelial cells in vitro. The injured cells were treated with geniposide (0. 128, 0.064, 0.032 micromol mL(-1), baicalin (0.028, 0.014, 0.007 micromol mL(- 1)) and berberine (0.024, 0.012, 0.006 micromol mL(-1)). The expression of p65 subunit of NF-kappaB was detected by immunocytochemical assay and techniques of image quantitative analysis. The protein expression of NF-kappaB was calculated with the mean optical density and mean area. The nuclear translocation of NF-kappaB was calculated with the percentage of positive cells and ratios of light transmittance of cytoplasm and cell nucleus. Compared with the normal group, both the protein expression and the nuclear translocation of NF-kappaB of model group were significant increased (P <0.01). Compared with the model group, the mean optical density of all treated groups was decreased ,but these was no significant difference between them. As compared with model group, the mean area of all treated groups was significant decreased (P < 0.01). The percentage of nuclear translocation of all treated groups is not only lower than that of the model group but higher than that of the normal group (P <0.01). Compared with the model group, the ratios of light transmittance of cytoplasm and cell nucleus of all treated groups was significantly elevated (P <0.01). The results suggesed that geniposide, baicalin and berberine could protect hypoxia/reoxygenation injuried rat cerebral microvascular endothelial cells injury. One of the mechanism may lie in inhibiting both the protein expression and the nuclear translocation of NF-kappaB.


Elbow Kinematics During Gait Improve With Age in Children With Hemiplegic Cerebral Palsy.
Children with hemiplegic cerebral palsy (hCP) exhibit a typical posture of elbow flexion during gait. However, the change in elbow kinematics and symmetry during gait across age span in both hCP and typically developing (TD) children is not well described. The aim of this study was to quantify the change in elbow kinematics and symmetry across age span in hCP children compared with TD children. Upper extremity kinematic data were extracted and analyzed from a database for gait studies performed between 2009 and 2015. A total of 35 hCP and 51 TD children between the ages of 4 and 18 (mean age: TD=11.2±0.6, hCP=9.8±0.5) met inclusionary criteria. The groups were further subdivided into 3 age categories: 4 to 7, 8 to 11, 12+ years old. Elbow angles were extracted and peak elbow flexion, overall range of motion during gait, and asymmetry indices were calculated. A 1-way analysis of variance was performed on each group with post hoc Tukey honestly significant difference pairwise comparisons. Peak elbow flexion during gait increased with age in TD children (P<0.05) and decreased with age in hCP children on the affected side (P<0.05). There was no change on the less affected side of hCP children. TD children demonstrated significantly less elbow flexion (mean=51.9±2.1 deg.) compared with the affected side in hCP (mean=82.1±3.8 deg.) across all age categories (P<0.05). There was no change in elbow asymmetry index (0=perfect symmetry) across age in either controls or hCP children; however, there were differences between hCP and TD groups in younger age groups (TD=28, hCP=62, P<0.05) that resolved by adolescence (TD=32, hCP=40). During gait, hCP children have greater peak elbow flexion on the affected side than do TD children. Peak elbow flexion angle converged between the 2 groups with age, decreasing in hCP children and increasing in TD children. Furthermore, elbow symmetry during gait improves with age in hCP children, approximating symmetry of TD children by adolescence. These findings have implications for both consideration and optimal timing of surgical intervention to improve elbow flexion in children with hCP. Level III-retrospective case-control study.


Ethyl 2-[3-(3,5-Dinitrobenzo-yl)thio-ureido]benzoate.
In the title compound, C(17)H(14)N(4)O(7)S, the dihedral angle between the two benzene rings is 9.04 (15)°. The centroid-centroid distance of 3.9825 (19) Å between nearly parallel benzene rings of adjacent mol-ecules suggests the existence of π-π stacking. Inter-molecular and intra-mol-ecular N-H⋯O hydrogen bonding is present in the structure. The eth-oxy group is disordered over two sets of sites with an occupancy ratio of 0.580 (15):0.420 (15). The crystal studied was an inversion twin.


Comparative assessment of the bioavailability, efficacy and safety of a modified-release (MR) carbonyl iron tablet and oral conventional iron preparation in adult Indian patients with nutritional iron deficiency anaemia.
The objective of the study is to evaluate the bioavailability, efficacy and safety of a new modified-release (MR) formulation of carbonyl iron (45 mg) relative to a commercially available conventional formulation of ferrous fumarate (300 mg) in adult Indian patients with clinical and laboratory diagnosis of nutritional iron deficiency anaemia. This prospective, comparative, randomised, double-blind study was carried out among 60 patients received a single daily dose of either MR carbonyl iron or ferrous fumarate for 12 weeks. The effect of therapy on haematological parameters and iron status and estimation of bioavailability were the main efficacy outcomes. There was a significant (p<0.05) increase in mean haemoglobin levels, reticulocyte counts, haematocrit and mean corpuscular volume in MR carbonyl iron group compared to ferrous fumarate group. There was also an increase in mean serum iron and ferritin levels and a corresponding decrease in total iron binding capacity in MR carbonyl iron group compared to ferrous fumarate group at the end of 12 weeks therapy. The estimated overall bioavailability of MR carbonyl iron was about 147% that of ferrous fumarate. Both the formulations were equally well-tolerated and adverse events were mainly gastrointestinal in nature. The prevalence of adverse events was slightly more in the ferrous fumarate group. It can be concluded that the MR formulation of carbonyl iron was more efficacious than ferrous fumarate in correcting haematologic abnormalities and improving iron status in patients with nutritional iron deficiency anaemia. In conditions where efficacy is an important consideration, the higher bioavailability of MR carbonyl iron may make it the treatment of choice for nutritional iron deficiency anaemia.


Potential role for a novel AP180-related protein during endocytosis in MDCK cells.
Clathrin assembly protein, AP180, was originally identified as a brain-specific protein localized to the presynaptic junction. AP180 acts to limit vesicle size and maintain a pool of releasable synaptic vesicles during rapid recycling. In this study, we show that polarized epithelial Madin-Darby canine kidney (MDCK) cells express two AP180-related proteins: the ubiquitously expressed 62-kDa clathrin assembly lymphoid myeloid leukemia (CALM, AP180-2) protein and a novel high-molecular-weight homolog that we have named AP180-3. Sequence analysis of AP180-3 expressed in MDCK cells shows high homology to AP180 from rat brain. AP180-3 contains conserved motifs found in brain-specific AP180, including the epsin NH2-terminal homology (ENTH) domain, the binding site for the alpha-subunit of AP-2, and DLL repeats. Our studies show that AP180-3 from MDCK cells forms complexes with AP-2 and clathrin and that membrane recruitment of these complexes is modulated by phosphorylation. We demonstrate by immunohistochemistry that AP180-3 is localized to cytoplasmic vesicles in MDCK cells and is also present in tubule epithelial cells from mouse kidney. We observed by immunodetection that a high-molecular-weight AP180-related protein is expressed in numerous cells in addition to MDCK cells.


The role of infection in COPD.
Clinical studies of acute exacerbations of COPD are difficult because of the heterogeneous nature of COPD, diffuse symptoms that can vary spontaneously, and difficulties in defining clinical response both in the short and long term. The role of bacterial infection, and thus use of antibiotics, in COPD is controversial. The available evidence shows that bacterial infection has a significant role in acute exacerbations, but its role in disease progression is less certain. Upper respiratory tract commensals, such as nontypable Haemophilus influenzae, cause most bronchial infections by exploiting deficiencies in the host defenses. Some COPD patients are chronically colonized by bacteria between exacerbations, which represents an equilibrium in which the numbers of bacteria are contained by the host defenses but not eliminated. When an exacerbation occurs, this equilibrium is upset and bacterial numbers increase, which incites an inflammatory response. Neutrophil products can further impair the mucosal defenses, favoring the bacteria, but if the infection is overcome, symptoms resolve. However, if the infection persists, chronic inflammation may cause lung damage. About half of exacerbations involve bacterial infection, but these patients are not easy to differentiate from those who are uninfected, which means that antibiotics have to be given more often than is strictly necessary. Further research is needed to characterize those patients in whom bacterial infection has a more important role.


Nereidid polychaetes as the major diet of migratory shorebirds on the estuarine tidal flats at Fujimae-higata in Japan.
The dietary items of five migratory shorebirds, Dunlin (Calidris alpina), Red-necked Stint (C. ruficollis), Grey Plover (Pluvialis squatarola), Whimbrel (Numenius phaeopus) and Black-headed Gull (Larus ridibundus), were examined by analyses of fecal droppings during the birds' migration or wintering and by surveys of macrobenthic fauna around their foraging sites on the tidal flats of Fujimae-higata, Nagoya, central Japan. Body parts of nereidid, capitellid, and spionid polychaetes and crustaceans were found in fecal droppings from all of these shorebirds. Two nereidid species (Hediste diadroma and Neanthes succinea) with relatively large body sizes seemed to be the majority dietary items. At one site, H. diadroma was dominant in terms of biomass (40-370 g/m(2)) throughout year except, for less than 1 g/m(2) in March and May (within or just after reproduction of this species). Monthly changes in the occurrence of food items in fecal droppings of C. alpina were examined in 1999 and 2000. Most (85-100%) of the fecal droppings contained nereidid body parts, including Hediste-specific simple chaetae from November to April, whereas only 23% of the droppings contained them in May. Chaetae of capitellid or spionid polychaetes were frequently found from January to April (38-86% of droppings). Crustacean body parts, including amphipod appendages, were frequently found from March to May (86-100% of droppings). The relationship between foraging habits of the shorebirds and the life history of their major prey nereidid species is discussed.


Hsa_circ_0018818 knockdown suppresses tumorigenesis in non-small cell lung cancer by sponging miR-767-3p.
To identify potential therapeutic targets in non-small cell lung cancer NSCLC, we conducted a bioinformatics analysis of circRNAs differentially expressed between NSCLC tissues and adjacent normal tissues. Cell proliferation and apoptosis was assessed using CCK-8 and flow cytometry, respectively. A connection between hsa_circ_0018818 and miR-767-3p was confirmed in dual luciferase reporter assays. Gene and protein expression in NSCLC cells were measured using quantitative PCR and Western-blotting, respectively. And a xenograft tumor model was established to assess the function of hsa_circ_0018818 in NSCLC in vivo. Hsa_circ_0018818 was greatly upregulated in NSCLC tumor tissues. Knocking down hsa_circ_0018818 using a targeted shRNA inhibited the proliferation and invasiveness of NSCLC cells and induced their apoptosis via the miR-767-3p/Nidogen 1 (NID1) signaling axis. Hsa_circ_0018818 knockdown also inactivated Epithelial-mesenchymal transition (EMT) process and PI3K/Akt signaling. In summary, hsa_circ_0018818 knockdown inhibited NSCLC tumorigenesis in vitro and in vivo, which suggests it could potentially serve as a target for the treatment of NSCLC.


Respiratory Neurophysiology in Intensive Care Unit.
Patients with intensive care unit-acquired weakness have an increased risk of prolonged mechanical ventilation, which is a risk factor for prolonged stay and mortality. The most common cause of this problem is weakness of the diaphragm, which can derive from phrenic nerve injury associated with critical neuropathy, or with the complex multiorgan failure/systemic respiratory response syndrome causing muscle fiber lesion. Two conventional neurophysiological techniques are useful to investigate the respiratory muscles, phrenic nerve conduction, and needle electromyography of the accessory respiratory muscles and diaphragm. Phrenic nerve stimulation is a standard noninvasive technique; amplitude of the motor response can be reduced because of muscle fiber inexcitability or axonal loss. Electromyography of the diaphragm is an invasive method but is safe if performed as indicated. It can reveal neurogenic or myopathic motor units. Although these neurophysiological methods have limitations in the investigation of intensive care unit patients with severe respiratory involvement, normal phrenic nerve responses should exclude marked axonal loss and indicate a better prognosis.


Effects of conjugated linoleic acid on growth, non-specific immunity, antioxidant capacity, lipid deposition and related gene expression in juvenile large yellow croaker (Larmichthys crocea) fed soyabean oil-based diets.
The effects of conjugated linoleic acid (CLA) on growth performance, non-specific immunity, antioxidant capacity, lipid deposition and related gene expression were investigated in the large yellow croaker (Larmichthys crocea). Fish (7·56 (SEM 0·60) g) were fed soyabean oil-based diets with graded levels of CLA (0, 0·42, 0·83, 1·70%) for 70 d. Quantitative PCR was used to assess the effects of CLA on the transcription of inflammation- and fatty acid oxidation-related genes. Growth in fish fed the diet with 0·42% CLA was significantly higher. Also, phagocytic index and respiratory burst activity were significantly higher in fish fed the diets containing 0·42 and 0·83% CLA, respectively. Hepatic total antioxidative capacity and catalase activities increased significantly when CLA increased from 0 to 0·83%, and then decreased with further increase of CLA. However, hepatic malondialdehyde content decreased significantly as dietary CLA increased. Lipid concentration in the whole body and muscle increased significantly with increasing dietary CLA. Transcription of genes related to inflammation (cyclo-oxygenase-2 and IL-b) in the liver and kidney and fatty acid oxidation (carnitine palmitoyl transferase I and acyl CoA oxidase) in the kidney decreased significantly as dietary CLA increased. PPAR alpha and acyl CoA oxidase expression in the liver decreased significantly as CLA increased from 0·42 to 1·70%. These results strongly suggest that dietary CLA could significantly affect growth performance, non-specific immunity, antioxidant capacity, lipid deposition and transcription of inflammation- and fatty acid oxidation-related genes of the large yellow croaker. This may contribute to our understanding of the mechanisms related to the physiological effects of dietary CLA in fish.


Secondary prevention of acute coronary events with antiplatelet agents (SPACE-AA): One-year real-world effectiveness and safety cohort study in the French nationwide claims database.
We aimed to compare the effectiveness of ticagrelor vs. clopidogrel or prasugrel on recurrence of acute coronary syndromes (ACS) in real-life conditions, as requested by regulatory authorities at the time of marketing. We performed a cohort study in SNDS, the French national healthcare database. All patients with a hospital admission for ACS in 2013 were followed one year. Patients on ticagrelor, clopidogrel or prasugrel were matched 1:1 using age, gender, index ACS type, and high-dimensional propensity scores (hdPS). Outcomes were ACS, stroke, all-cause death, and major bleeding, compared within matched groups using Cox proportional hazards models analysis during treatment. 54,048 ACS were hospitalized in 2013. At discharge, 19,796 were dispensed clopidogrel, 8242 prasugrel, and 13,916 ticagrelor. Per group, 9224 ticagrelor vs. clopidogrel, 6752 ticagrelor vs. prasugrel, and 4676 prasugrel vs. clopidogrel patients were matched. Compared to clopidogrel, ticagrelor was associated with a lower hazard ratio of death 0.73 [0.59-0.90] and composite criterion (0.88, 95% CI [0.79-0.99] but not ACS 0.92 [0.80-1.06], stroke (0.96 [017-5.53]) or major bleeding (1.02 [0.82-1.26]). Prasugrel was not different from ticagrelor or clopidogrel for any outcome, in matched patients. Ticagrelor in real-life conditions in matched populations was associated with a lower risk of all-cause death than clopidogrel, and a lower risk of composite outcome, as in the main pivotal clinical trial. Ticagrelor and prasugrel were not different, nor were prasugrel and clopidogrel.


[Effect of oxygen deprivation on photosensitivity and thermostability of Drosophila].
There are certain distinctions in firmness to the high temperature and photo sensitiveness between highly and low steady to the hypoxia action of flies. Flies of line Conton-S after preadaptation to hypoxia acquired more firmness to the high temperature. Most of flies in line Uman, who are high-steady to the action of hypoxia, had positive phototaksis. It goes to show that firmness to the high temperature and phototaksis flies Drosophila are genetically programmed and passed on an inheritance.


Effects of inhalation exposure to propylene oxide on respiratory tract, reproduction and development in rats.
Nasal, respiratory, reproductive and developmental toxicities of propylene oxide (PO) were examined by exposing male and female Sprague-Dawley rats to PO vapor by inhalation at a concentration of 0 (control), 125, 250, 500 or 1,000 ppm for 6 h/d, 7 d/wk, during a 5- to 6-wk period, including premating, mating and postmating or gestation. The inhalation exposure to 1,000 ppm PO seriously affected parental survival, the upper and lower respiratory tract, male and female reproductive systems, motor function, and fetal survival and development, whereas the exposure to 500 ppm or less primarily caused nasal lesions without any sign of reproductive or developmental toxicity. Because atrophy of the olfactory epithelium in the male rats exposed to 250 ppm was the most sensitive endpoint for PO toxicity, the NOAEL was determined to be 125 ppm for the nasal endpoint. An additional inhalation experiment was carried out to further examine developmental toxicity by exposing pregnant rats to 0, 125, 250, 500, 750 or 1,000 ppm PO during a 2-wk period of gestation, Day 6 through Day 19. The 2-wk inhalation experiment revealed that reduced fetal body weights and delayed ossification occurred in association with significantly reduced body weights of the dams exposed to 750 and 1,000 ppm, whereas neither fetal death nor teratogenicity occurred at those two exposure levels. It was concluded that the developmental toxicity of fetal death was manifested at parentally toxic exposure levels above 500 ppm, a level which seriously affected parental survival, the upper and lower respiratory tracts and reproductive system.


Features of the sampling distribution of the ability estimate in computerized adaptive testing according to two stopping rules.
Whether paper and pencil or computerized adaptive, tests are usually described by a set of rules managing how they are administered: which item will be first, which should follow any given item, when to administer the last one. This article focus on the latter and looks at the effect of two stopping rules on the estimated sampling distribution of the ability estimate in a CAT: the number of items administered and the a priori determined size of the standard error of the ability estimate.


Cross-validation of genes potentially associated with overall survival and drug resistance in ovarian cancer.
Ovarian cancer is the leading cause of death among malignancies of the female reproductive system. The 5-year survival rates of ovarian cancer (OC) patients are very poor as a result of recurrent disease and emergence of drug resistance; thus, studies to find predictive markers and factors for drug resistance are ongoing. In the present study, based on the microarrays from The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) profiles covering 1648 OC patients, 11 out of 136 genes that were found to be significantly dysregulated in OC were associated with overall survival (OS) in 489 OC patients of the TCGA cohort. Of these genes, CRISP3, LYVE1, OVGP1 and BCHE were identified as independent prognostic factors, with decreased expression of the first three genes predicting shorter OS, and decreased BCHE predicting longer OS. OVGP1, BCHE and further two genes, CKAP2 and CLDN10, were consistently and remarkably associated with OS when the number of patients increased from 489 to 1583, with increased CKAP2 and decreased CLDN10 predicted shorter OS; combining the four genes provided better predictions. Associations among the four genes with OS in subgroups of OC were further verified. Downregulation of OVGP1 was significantly associated with shorter OS in all subgroups of OC patients, including subgroups of 752 patients treated with chemotherapy regimens containing taxol, 763 with both platin and taxol, 1364 with platin, 371 patients with grade 1-2 disease, 968 with grade 3 disease, 1148 with stage III-IV disease, and 439 with TP53 mutations. In addition, CKAP2 expression was significantly associated with shorter OS in 515 OC patients who had low CA125 levels. Furthermore, comprehensive analyses that including RT-qPCR, bioinformatics analysis and clinical data revealed an association of CKAP2, BCHE, CLDN10 and OVGP1 with drug resistance in OC. The genes identified in the present study might be prognostic factors as well as potential therapeutic targets in the treatment of OC.


[2 + 1 + 1] Assembly of spiro β-lactams by Rh(ii)-catalyzed reaction of diazocarbonyl compounds with azirines/isoxazoles.
A domino synthesis of dispiro-fused N-vinyl β-lactams from diazo-Meldrum's acid and 2H-azirines or 5-alkoxyisoxazoles via the "2-azabuta-1,3-diene formation/Staudinger ketene-imine cycloaddition" sequence is described. The Rh2(Piv)4-catalyzed formation of the 2-azabuta-1,3-diene intermediates in the first stage of the reaction sequence proceeds via addition of the rhodium carbenoid to the azirines/isoxazoles and provides the first example of the generation of iminium-type ylides from diazo-Meldrum's acid. This methodology was extended to monospiro-β-lactams, which were synthesized in two steps using acyclic α-diazocarbonyl compounds in the stage of the formation of 2-azabuta-1,3-dienes. The method allows for the rapid assemblage of the carbon part of the azetidin-2-one system from diazo compounds only and affords spiro- and dispiro-β-lactams in moderate yields. A bromine atom in the 2-bromoalkenyl moiety of the synthesized β-lactams can be easily substituted by hydrogen under catalytic hydrogenation conditions or by 2-pyridyl-substituent via the Stille cross-coupling reaction.


Future trends in the treatment of rheumatoid arthritis in the light of current etiopathogenetic theories.
The current treatment of rheumatoid arthritis is based on the use of synthetic chemical compounds, the mechanism and action of which have been more or less unknown. Usually this therapeutic effectiveness was discovered accidentally. Often the initial use of such compounds was motivated on the basis of generally diffuse ideas about the eventual pathogenesis of rheumatoid arthritis. The main site of action of most of these drugs has recently been elucidated. Depending on their multiple sites of action the polypharmacy frequency relied upon at present seems also to be theoretically motivated. Many new possibilities for treatment which have appeared recently have resulted from the amission of page limitation. These include various thymic (46), steroid and other hormones (67) and various vehicles or new modes of application, e.g. percutaneous, for directing the effects of drugs selectively to the target tissue, organ and cells. The use of specific T cell clones in therapy (68) has been only briefly dealt with in this article, and the development of operative techniques, endoprosthesis technology and orthopedic devices have not been dealth with at all. Chemical synovectomies with 165Dy-FHMA and other agents (69) will be developed further etc. This overview mainly deals with future trends in the treatment of rheumatoid arthritis based on advances made in the evaluation of the etiopathogenesis. Due to advances in basic sciences and medicine, the pathogenetic mechanisms effective in rheumatoid arthritis are better known today than ever before. The same progress in science has for the first time in history provided us with a potential means of producing bioactive mediators and reagents in sufficient amounts to enable their use also for therapeutic trials and treatment. In addition to the need to develop better methods of treatment for the patients crippled by this chronic disease, studies on the pathogenesis will also be of great benefit to our ideas about exactly what is involved in the complex process clinically known as rheumatoid arthritis.


Sympatrically breeding congeneric seabirds (Stercorarius spp.) from Arctic Canada migrate to four oceans.
Polar systems of avian migration remain unpredictable. For seabirds nesting in the Nearctic, it is often difficult to predict which of the world's oceans birds will migrate to after breeding. Here, we report on three related seabird species that migrated across four oceans following sympatric breeding at a central Canadian high Arctic nesting location. Using telemetry, we tracked pomarine jaeger (Stercorarius pomarinus, n = 1) across the Arctic Ocean to the western Pacific Ocean; parasitic jaeger (S. parasiticus, n = 4) to the western Atlantic Ocean, and long-tailed jaeger (S. longicaudus, n = 2) to the eastern Atlantic Ocean and western Indian Ocean. We also report on extensive nomadic movements over ocean during the postbreeding period (19,002 km) and over land and ocean during the prebreeding period (5578 km) by pomarine jaeger, an irruptive species whose full migrations and nomadic behavior have been a mystery. While the small sample sizes in our study limit the ability to make generalizable inferences, our results provide a key input to the knowledge of jaeger migrations. Understanding the routes and migratory divides of birds nesting in the Arctic region has implications for understanding both the glacial refugia of the past and the Anthropocene-driven changes in the future.


The use of the Veress needle to drain mammary periprosthetic fluid.
The most common early complications associated with mammary implants are seroma and haematoma formation, and acute infection. The aspiration of fluid around the prosthesis can help to diagnose and correctly treat these complications. The use of a needle with a sharp tip can damage the implant. We present our experience in removing periprosthetic fluid using the atraumatic Veress needle. Twelve patients with breast implants presented with a progressive monolateral breast enlargement. Ultrasound examination revealed the collection of fluid around the implants. Ultrasound-guided percutaneous needle aspiration of the fluid was performed using the Veress needle. No complications were reported. None of the implants was found to be damaged at the ultrasound assessment. Our proposed use of the Veress needle is similar to the use for which it was designed. Indeed, we used the device to remove some fluid from a real cavity. This procedure proved to be effective and safe.


Pulmonary function patterns and their association with genotype and phenotype in adult cystic fibrosis patients.
Background: While cystic fibrosis (CF) lung disease is generally considered to be an obstructive disorder, other pulmonary function patterns (PFP) may occur. Furthermore, little is known about possible associations between PFP and genotype or phenotypical characteristics. Methods: Cross-sectional study including CF patients aged 16 years or more, identifying different PFP and exploring associations between PFP and genotype or phenotypical characteristics. Results: Obstructive PFP was most prevalent in our population (n = 80), comprising obstructive lung disease (62.5%), small airway (obstructive) disease (11.2%), and mixed obstructive-restrictive disorder (1.3%). However, one in four adult CF patients did not show any obstruction at all: normal (13.7%) or restrictive (8.8%) lung disease and isolated diffusion disorder (2.5%). Obstructive PFP was associated with a greater proportion of CF-related diabetes mellitus (CFRD) (P = 0.04), Pseudomonas aeruginosa colonization (P = 0.02) and frequent exacerbators (P = 0.04). We observed no association between PFP and genotype. Conclusions: Obstructive PFP remains the most common pulmonary function pattern in adult CF and is associated with CFRD, Pseudomonas aeruginosa colonization and frequent exacerbators.


The effect of the oral contraceptive pill on the passive stiffness of the human gastrocnemius muscle in vivo.
The aim of this investigation was to determine the effect of sustained monophasic oral contraceptive pill (MOCP) use on the in vivo passive stiffness of the gastrocnemius medialis (GM) muscle-tendon unit. Twenty four females volunteered for this study (age range 20-25 yrs); twelve participants had been taking the combined MOCP for a minimum of 12 months, and twelve participants, who had never taken the MOCP, formed a control group. Distal displacement of the GM myotendinous junction (MTJ) was measured during passive dorsiflexion at 2 Nm increments to 20 Nm, and at end range of motion using ultrasonography. In addition, GM MTJ displacement was measured at passive torques equivalent to 5, 10 and 15% of plantarflexion maximal voluntary contraction (MVC) torque, and relative to GM length. MOCP users had significantly greater GM MTJ displacement at all passive torques (P<0.01), reaching 40% more at 20 Nm; these displacements remained significantly different when MVC and GM length were accounted for (P<0.01). Passive muscle stiffness from 0-20 Nm was 31% less in MOCP users compared to non-users (P<0.01). In conclusion, based on the in vivo assessment of GM MTJ displacement, passive muscle stiffness is less in MOCP using females, compared to non-pill users.


Electrochemical detection of single-nucleotide mismatches: application of M-DNA.
The detection of a single-nucleotide mismatch in unlabeled duplex DNA by electrochemical methods is presented. Impedance spectroscopy is used to characterize a perfect duplex monolayer and three DNA monolayers differing in the position of the mismatch. The monolayers were studied as B-DNA (normal duplex DNA) and after conversion to M-DNA (a metalated duplex). Modeling of the impedance data to an equivalent circuit provides parameters that are useful in discriminating the four monolayer configurations. The resistance to charge transfer, R(CT), was lower for all duplexes after conversion to M-DNA. Contrary to expectations, R(CT) was also found to decrease for duplexes containing a mismatch. However, R(CT) was found to be diagnostic for mismatch detection. In particular, the difference in R(CT) between B- and M-DNA (deltaR(CT)) decreased from 190(22) omega.cm(2) for a perfectly matched duplex to 95(20), 30(20), and 85(20) omega.cm(2) for a mismatch at the top (distal), middle, and bottom (proximal) positions of the monolayer with respect to the gold surface. Further, a method to form loosely packed single-stranded (ss)-DNA monolayers by duplex dehybridization that is able to rehybridize to target strands is presented. Rehybridization efficiencies were in the range of 40-70%. Under incomplete hybridization conditions, the R(CT) was the same for matched and mismatched duplexes under B-DNA conditions. However, deltaR(CT) between B- and M-DNA, under incomplete hybridization, still provided a distinction. The deltaR(CT) for a perfect duplex was 76(12) omega.cm(2), whereas a mismatch in the middle of the sequence yielded a deltaR(CT) value of 30(15) omega.cm(2). The detection limit was measured and the impedance methodology reliably detected single DNA base pair mismatches at concentrations as low as 100 pM.


Lymphoid signal transduction mechanisms linked to cellular prion protein.
The normal cellular isoform of the prion protein (PrPC) is a glycosylphosphatidylinositol-anchored cell surface protein that is expressed widely, including in lymphoid cells. We compared lectin-induced mitogenesis and selected cell signaling pathways in splenocytes from wild-type BALB/c mice and Zrch Prnp0/0 (PrP0/0) mice bred on a BALB/c background for more than 10 generations. 3H-thymidine incorporation induced by concanavalin A (Con A) or phytohemagglutinin (PHA) was significantly reduced in PrP0/0 splenocytes, most prominently early in activation (24 and 48 h). Con A activation in PrP0/0 splenocytes was associated with differences in the phosphorylation (P) patterns of protein kinase C (PKC alpha/beta, but not delta) and the PKC downstream effectors p44/42MAPK (mitogen-activated protein kinase). P-PKC and P-MAPK profiles were similar in wild-type and PrP0/0 splenocytes following PMA treatment, indicating that the ability of these 2 enzymes to be phosphorylated is not impaired in the absence of PrPC. Con A-induced calcium fluxes, monitored by indo-1 fluorescence, were equivalent in PrP0/0 and PrP+/+ splenocytes, suggesting that calcium-dependent mechanisms are not directly implicated in the differential phosphorylation patterns or mitotic responses. Our data indicate that PrP0/0 splenocytes display defects in upstream or downstream mechanism(s) that modulate PKCalpha/beta phosphorylation, which in turn affects its capacity to regulate splenocyte mitosis, consistent with a role for PrPC in immune function.


Hypoxia-activated prodrug enhances therapeutic effect of sunitinib in melanoma.
Angiogenesis is a critical step during tumor progression. Anti-angiogenic therapy has only provided modest benefits in delaying tumor progression despite its early promise in cancer treatment. It has been postulated that anti-angiogenic therapy may promote the emergence of a more aggressive cancer cell phenotype by generating increased tumor hypoxia-a well-recognized promoter of tumor progression. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) which has been shown to selectively target the hypoxic tumor compartment and reduce tumor volume. Here, we show that melanoma cells grown under hypoxic conditions exhibit increased resistance to a wide variety of therapeutic agents in vitro and generate larger and more aggressive tumors in vivo than melanoma cells grown under normoxic conditions. However, hypoxic melanoma cells exhibit a pronounced sensitivity to TH-302 which is further enhanced by the addition of sunitinib. Short term sunitinib treatment fails to prolong the survival of melanoma bearing genetically engineered mice (Tyr::CreER; BRafCA;Ptenlox/lox ) but increases tumor hypoxia. Long term TH-302 alone modestly prolongs the overall survival of melanoma bearing mice. Combination therapy of TH-302 with sunitinib further increases the survival of treated mice. These studies provide a translational rationale for combining hypoxic tumor cell targeted therapies with anti-angiogenics for treatment of melanoma.


Learning subjective health complaints.
Symptom episodes often show a spatio-temporal structure, that is, they occur in a specific context for a certain duration. Repeated experiences may therefore be construed as associative learning trials, in which context elements are turned into predictive cues, triggering anticipatory processes conducive to subjective health complaints. A series of experiments, using inhalations of air enriched with CO2 and external (odors) or internal (mental images) stimuli as cues, is discussed to show that subjective health complaints may occur upon presenting the cue alone. Learned symptoms may be unrelated to bodily responses and easily generalize to new related cues. Better learning occurs to cues with a negative affective valence and in participants scoring high for negative affectivity. Our findings are relevant to the understanding of medically unexplained ("functional") syndromes and the poor relationship between objective and subjective health indicators in general.


Vascular and metabolic effects of the haem oxygenase-1 inducer haem arginate in subjects with the metabolic syndrome: A translational cross-over study.
This translational randomized and vehicle-controlled cross-over study was performed to assess the impact of haem arginate treatment on haem oxygenase-1 induction, endothelial function and insulin sensitivity in subjects with the metabolic syndrome (n = 14). Both treatment periods consisted of 5 days. Haem arginate or vehicle (l-arginine) was administered intravenously on Days 1 and 3. Forearm blood flow in response to acetylcholine and nitroglycerine was measured by venous occlusion plethysmography (Day 3), insulin sensitivity by a hyperinsulinaemic clamp procedure (Day 5). Haem arginate did not improve endothelial function or insulin sensitivity but significantly reduced the vasodilator response to nitroglycerine (p < 0.01). These negative findings are in contrast to the preclinical data, which may be due to short duration of therapy and limited haem oxygenase-1 induction as well as interference by markedly elevated plasma haem levels observed after haem arginate treatment (p < 0.01). Future studies should pay attention to the delicate balance between sufficient dosing and timely normalization of plasma haem levels.


Microneedle and mucosal delivery of influenza vaccines.
In recent years with the threat of pandemic influenza and other public health needs, alternative vaccination methods other than intramuscular immunization have received great attention. The skin and mucosal surfaces are attractive sites probably because of both noninvasive access to the vaccine delivery and unique immunological responses. Intradermal vaccines using a microinjection system (BD Soluvia(TM)) and intranasal vaccines (FluMist®) are licensed. As a new vaccination method, solid microneedles have been developed using a simple device that may be suitable for self-administration. Because coated microneedle influenza vaccines are administered in the solid state, developing formulations maintaining the stability of influenza vaccines is an important issue to be considered. Marketable microneedle devices and clinical trials remain to be developed. Other alternative mucosal routes such as oral and intranasal delivery systems are also attractive for inducing cross-protective mucosal immunity, but effective non-live mucosal vaccines remain to be developed.


Exciton scattering approach for branched conjugated molecules and complexes. I. Formalism.
We develop a formalism for the exciton scattering (ES) approach to calculation of the excited state electronic structure of branched conjugated polymers with insignificant numerical expense. The ES approach attributes electronic excitations in quasi-one-dimensional molecules to standing waves formed by the scattering of quantum quasiparticles. We derive the phenomenology from the microscopic description in terms of many-electron excitations. The presented model can be used to compute both excited state frequencies and transition dipoles in large molecules after the ES ingredients are extracted from smaller molecular fragments.