Microbial ecology of Campylobacter jejuni in a United Kingdom chicken supply chain: intermittent common source, vertical transmission, and amplification by flock propagation.
A study of Campylobacter jejuni on a broiler chicken farm between 1989 and 1994 gave an estimated isolation rate of 27% (3,304 of 12,233) from a 0.9% sample of 1.44 million broiler chickens from six to eight sheds over 32 consecutive rearing flocks comprising 251 broiler shed flocks. During the study, C. jejuni was found in 35.5% of the 251 shed flocks but only 9.2% (23 of 251) had Campylobacter isolates in successive flocks, with 9 of those 23 sheds having the same serotype between consecutive flocks, indicating a low level of transmission between flocks. Analysis of a systematic sample of 484 of 3,304 (14.6%) C. jejuni isolates showed that 85% were of 10 serotype complexes but 58% were of 3 serotype complexes, indicating a high degree of strain similarity throughout the entire study. The three commonest types were detected in 8 of 32 flocks during the 5-year study period, suggesting an intermittent common external Campylobacter source. This hypothesis was tested by a retrospective cohort analysis of C. jejuni rates and types by reference to hatchery supplier of the 1-day-old chicks. Isolation rates of C. jejuni and frequency distribution of types were determined in 6-week-old broiler chickens identified by the hatchery supplying the original chicks. The isolation rate of C. jejuni in broilers, supplied by hatchery A, was 17.6%, compared to 42.9% (P < 0.0001) for broilers reared from chicks supplied by hatchery B. In two instances, when both hatcheries were used to stock the same farm flock, Campylobacter isolates were found only in those sheds with chicks supplied by hatchery B. Thus, the frequency distribution of Campylobacter types for chickens supplied by the two hatcheries over the 5-year period showed marked dissimilarity. These findings suggest that the isolation rate and type of Campylobacter isolates in broiler chickens was associated with the hatchery supplying chicks. The lack of diversity of types and the intermittent high positivity of sheds is evidence for a common source of C. jejuni introduced by vertical transmission rather than contamination at the hatchery or during transportation.


Vaccine Development against COVID-19: Study from Pre-Clinical Phases to Clinical Trials and Global Use.
As per the World Health Organization (WHO), more than 288 vaccines against COVID-19 are being developed, with an estimated 184 being presently investigated in the pre-clinical phases, while 104 of these vaccine candidates are at various stages of clinical trials. Twelve of these are in the advanced stages of clinical investigation, and promising results in the phase 3 trials have already paved the way for their regulatory approval and subsequent dissemination for global use. Preliminary and interim results of some of these candidate vaccines are being analyzed for public dissemination. Some of these vaccines have already been rolled out to immunize not only the highest risk individuals but also the general population in several countries. Once their safety and efficacy are established, the next limiting step would be their mass manufacturing by the pharmaceutical companies to fulfill the global demand. The challenge of manufacturing billions of doses of high-quality vaccines is under-appreciated at the moment. A massive vaccination drive would be needed to protect people of all ages. The timely and coordinated execution of the vaccination effort would require unprecedented coordination at the national and international levels for generating funds to purchase the required doses of vaccines, fair distribution of doses and managing the mechanics of delivering vaccines throughout the world.


Membrane Curvature and Lipid Composition Synergize To Regulate N-Ras Anchor Recruitment.
Proteins anchored to membranes through covalently linked fatty acids and/or isoprenoid groups play crucial roles in all forms of life. Sorting and trafficking of lipidated proteins has traditionally been discussed in the context of partitioning to membrane domains of different lipid composition. We recently showed that membrane shape/curvature can in itself mediate the recruitment of lipidated proteins. However, exactly how membrane curvature and composition synergize remains largely unexplored. Here we investigated how three critical structural parameters of lipids, namely acyl chain saturation, headgroup size, and acyl chain length, modulate the capacity of membrane curvature to recruit lipidated proteins. As a model system we used the lipidated minimal membrane anchor of the GTPase, N-Ras (tN-Ras). Our data revealed complex synergistic effects, whereby tN-Ras binding was higher on planar DOPC than POPC membranes, but inversely higher on curved POPC than DOPC membranes. This variation in the binding to both planar and curved membranes leads to a net increase in the recruitment by membrane curvature of tN-Ras when reducing the acyl chain saturation state. Additionally, we found increased recruitment by membrane curvature of tN-Ras when substituting PC for PE, and when decreasing acyl chain length from 14 to 12 carbons (DMPC versus DLPC). However, these variations in recruitment ability had different origins, with the headgroup size primarily influencing tN-Ras binding to planar membranes whereas the change in acyl chain length primarily affected binding to curved membranes. Molecular field theory calculations recapitulated these findings and revealed lateral pressure as an underlying biophysical mechanism dictating how curvature and composition synergize to modulate recruitment of lipidated proteins. Our findings suggest that the different compositions of cellular compartments could modulate the potency of membrane curvature to recruit lipidated proteins and thereby synergistically regulate the trafficking and sorting of lipidated proteins.


Effects of surface conditioning on repair bond strengths of non-aged and aged microhybrid, nanohybrid, and nanofilled composite resins.
This study evaluates effects of aging on repair bond strengths of microhybrid, nanohybrid, and nanofilled composite resins and characterizes the interacting surfaces after aging. Disk-shaped composite specimens were assigned to one of three aging conditions: (1) thermocycling (5,000 ×, 5-55 °C), (2) storage in water at 37 °C for 6 months, or (3) immersion in citric acid at 37 °C, pH 3 for 1 week; a non-aged group acted as the control. Two surface conditionings were selected: intermediate adhesive resin application (IAR-application) and chairside silica coating followed by silanization and its specific IAR-application (SC-application). Composite resins, of the same kind as their substrate, were adhered onto the substrates, and repair shear bond strengths were determined, followed by failure type evaluation. Filler particle exposure was determined by X-ray photoelectron spectroscopy and surface roughness analyzed using scanning electron and atomic force microscopy. Surface roughness increased in all composite resins after aging, but filler particle exposure at the surface only increased after thermocycling and citric acid immersion. Composite resin type, surface conditioning, and aging method significantly influenced the repair bond strengths (p < 0.05, three-way analysis of variance) with the least severe effects of water storage. Repair bond strengths in aged composite resins after IAR-application were always lower in non-aged ones, while SC-application led to higher bond strengths than IAR-application after thermocycling and water storage. In addition, SC-application led to more cohesive failures than after IAR-application, regardless the aging method.


[Effect of strophanthin on the electrophoretic mobility of blood erythrocytes in adults and children].
As assessed by changes in the erythrograms asymmetry coefficient, selectivity of the strophantin effect on cell populations with different mobility and age specifics of reciprocal responses, was revealed in adult subjects and in children. The data obtained suggest existence of difference in quality of functional condition of the erythrocytes with normal as well as reduced mobility in children and in adults.


Correction of cortisol overreplacement ameliorates morbidities in patients with hypopituitarism: a pilot study.
Hypopituitarism in adults is known to be associated with deleterious effects on body composition, lipid profile and quality of life (QoL). This was attributed to GH deficiency. The potential role of glucocorticoid overreplacement had never been investigated. To investigate whether reduction in glucocorticoid replacement dose to more physiological one could ameliorate the "AO-GHD"-attributed symptomatology in patients with hypopituitarism. Design Eleven patients with panhypopituitarism taking 20-30 mg/day of hydrocortisone, but on no GH replacement were switched to 10-15 mg of hydrocortisone daily. Both basally and 6-12 months later, their body mass index, body composition by dual-energy X-ray absorptiometry, lipid profile, and the score of quality of life, QOL-AGHDA were measured. Within 6-12 months of lower hydrocortisone dose, subjects lost an average of 7.1 kg of total body fat and 4.1 kg of abdominal fat. No changes were seen in lean body mass, bone mineral content and HOMA-IR. Plasma total cholesterol and triglyceride concentrations decreased significantly (< 0.05) and the QoL improved (P = 0.018). Our pilot study suggests that decreasing the glucocorticoid replacement dose to approximately 15 mg/day is beneficial in terms of patients' body composition, lipid profile and quality of life.


FOXO3a Mediates Homologous Recombination Repair (HRR) via Transcriptional Activation of MRE11, BRCA1, BRIP1, and RAD50.
To test whether homologous recombination repair (HRR) depends on FOXO3a, a cellular aging model of human dermal fibroblast (HDF) and tet-on flag-h-FOXO3a transgenic mice were studied. HDF cells transfected with over-expression of wt-h-FOXO3a increased the protein levels of MRE11, BRCA1, BRIP1, and RAD50, while knock-down with siFOXO3a decreased them. The protein levels of MRE11, BRCA1, BRIP1, RAD50, and RAD51 decreased during cellular aging. Chromatin immunoprecipitation (ChIP) assay was performed on FOXO3a binding accessibility to FOXO consensus sites in human MRE11, BRCA1, BRIP1, and RAD50 promoters; the results showed FOXO3a binding decreased during cellular aging. When the tet-on flag-h-FOXO3a mice were administered doxycycline orally, the protein and mRNA levels of flag-h-FOXO3a, MRE11, BRCA1, BRIP1, and RAD50 increased in a doxycycline-dose-dependent manner. In vitro HRR assays were performed by transfection with an HR vector and I-SceI vector. The mRNA levels of the recombined GFP increased after doxycycline treatment in MEF but not in wt-MEF, and increased in young HDF comparing to old HDF, indicating that FOXO3a activates HRR. Overall, these results demonstrate that MRE11, BRCA1, BRIP1, and RAD50 are transcriptional target genes for FOXO3a, and HRR activity is increased via transcriptional activation of MRE11, BRCA1, BRIP1, and RAD50 by FOXO3a.


A new species of Dipetalonema (Filarioidea: Onchocercidae) from Ateles chamek from the Beni of Bolivia.
We describe a new species of Dipetalonema occurring in the body cavity of Ateles chamek (Humboldt, 1812) from north-central Bolivia. Morphologic characters serving to separate Dipetalonema yatesi n. sp. from known forms include a vagina vera with a simple tube and thin walls and a left spicule, which possesses a handle shorter than the lamina (ratio 2.7); the latter displays an anterior membranous alae similar in length to the terminal flagellum, a distal extremity of the left spicule within a simple hook and a membrane, phasmids at the basis of the lappets, and heterogeneous muscles occupying the whole cavity. Dipetalonema yatesi n. sp. can be separated from Dipetalonema robini, Dipetalonema gracile, and Dipetalonema graciliformis, between other characters, in having a simple vagina vera instead of a sinuous one, and from Dipetalonema caudispina and Dipetalonema freitasi in having the lamina of the left spicule divided in a membranous alae and a terminal flagellum.


Expression of ERCC1 and BRCA1 predict the clinical outcome of non-small cell lung cancer in patients receiving platinum-based chemotherapy.
We examined mRNA expression levels of ERCC1, BRCA1, RRM1, and human β-tubulin-III (TUBB3) in non-small-cell lung carcinoma (NSCLC) patients and investigated the association between expression of these genes and the clinical outcome of NSCLC treatment. A total of 366 patients who underwent surgery for NSCLC were included in this study. All patients received third-generation platinum-based chemotherapy as first-line treatment. The relative cDNA quantification for ERCC1, RRM1, BRCA1, and TUBB3 was determined using a fluorescence-based, real-time detection method. We found that low expression of ERCC1 and BRCA1 was associated with a good response to platinum-based chemotherapy, with an odds ratio [95% confidence interval (CI)] of 2.09 (1.33-3.27) and 2.92 (1.85-4.62), respectively. Multivariate Cox regression analysis indicated that patients with low expression of ERCC1 and BRCA1 attained a longer overall survival time than those with high expression, with a hazard ratio (95%CI) of 0.42 (0.23-0.77) and 0.39 (0.21-0.71), respectively. However, RMM1 and TUBB2 expressions were not correlated with clinical outcome of NSCLC. In conclusion, we found that low expression of ERCC1 and BRCA1 can be useful for selecting NSCLC patients who would benefit from chemotherapy and warrants further investigation in prospective studies.


Antigraft antibody-mediated expression of metalloproteinases on endothelial cells. Differential expression of TIMP-1 and ADAM-10 depends on antibody specificity and isotype.
Endothelial cell (EC) interaction with antigraft antibodies (Abs) mediates EC injury and activation involved in vascular graft rejection. The aim of this study was to identify EC genes regulated in response to antigraft Ab binding that contribute to the endothelium alterations implicated in graft rejection or survival. By means of RNA differential display, 13 cDNA fragments corresponding to genes differentially expressed in ECs incubated with antigraft Abs were identified. Among these cDNAs were found the tissue inhibitor of metalloproteinase-1 (TIMP-1) and a desintegrin and metalloproteinase (ADAM-10). We demonstrated that TIMP-1 and ADAM-10 mRNA and protein expression was rapidly upregulated in ECs in response to antigraft Ab binding. Our data showed that TIMP-1 was upregulated in response to human IgG but not IgM and anti-galactosyl (Gal) alpha1-3Gal human xenogeneic Abs. In contrast, upregulation of ADAM-10 in ECs was shown to be mostly mediated by anti-Galalpha1-3Gal IgM Abs. Specific effects of human IgG and IgM xenogeneic Abs on endothelial transcripts indicate that different isotypes and specificities of Abs may mediate different EC changes. Our results suggest that interaction of ECs with antigraft Abs, according to their specificity, selectively induces synthesis and release of metalloproteinases and inhibitors, controlling proteolytic processes and immunological events that respectively contribute to graft rejection or survival.


Modular Connections between Areas V2 and V4 of Macaque Monkey Visual Cortex.
We have studied the connections between two visual areas of macaque monkey cortex, V2 and V4, by injecting wheat-germ agglutinin horseradish peroxidase (HRP-WGA) into V4 and examining the distribution of labelled cells and terminals in V2, in relation to its characteristically striped cytochrome oxidase architecture. The cells projecting from V2 to V4 are arranged in bands and the number of bands per cycle of cytochrome oxidase stripes varies (one cycle consists of a thin stripe, a thick stripe and two interstripes). In the Type 1 connectivity pattern, there is just one band per cycle, centred over the thin stripes but normally spreading into the neighbouring interstripes. In the Type 2 connectivity pattern there are two bands per cycle, generally rather narrower and centred over the interstripes. Thick stripes are mostly free of labelled cells. The return projection from V4 to V2, whilst being concentrated in the vicinity of the labelled cells, is more diffusely distributed and invades the territory of all the stripes.


Prevalence of Sleep Deprivation and Relation with Depressive Symptoms among Medical Residents in King Fahd University Hospital, Saudi Arabia.
Sleep deprivation is common among medical residents of all specialties. This study aimed to determine the prevalence of sleep deprivation and depressive symptoms among medical residents in King Fahd University Hospital (KFUH) in Al Khobar, Saudi Arabia. Furthermore, the association between sleep deprivation, sleepiness and depressive symptoms was examined. This cross-sectional study took place between February and April 2012 and involved 171 KFUH medical residents of different specialties. Data were collected using a specifically designed questionnaire eliciting demographic information, working hours and number of hours of sleep. In addition, validated Arabic versions of the Epworth Sleepiness Scale and the Beck Depression Inventory-2 (BDI-2) were used. The prevalence of acute sleep deprivation and chronic sleep deprivation among residents in KFUH was 85.9% and 63.2%, respectively. The prevalence of overall sleepiness was 52%; 43.3% reported being excessively sleepy in certain situations while 8.8% reported being excessively sleepy regardless of the situation. Based on the BDI-2, the prevalence of mild, moderate and severe depressive symptoms was 43.3%, 15.2% and 4.7%, respectively. Significant associations were found between sleep deprivation and depressive symptoms; depressive symptoms and sleepiness, and depressive symptoms and being a female resident. The vast majority of medical residents had acute sleep deprivation, with more than half suffering from chronic sleep deprivation. The number of hours and quality of sleep among the residents were strongly associated with depressive symptoms. New regulations are recommended regarding the number of working hours and night duties for medical residents. Further studies should assess these new regulations on a regular basis.


Approaches to understanding the relationship between diet and colon cancer.
Epidemiological research into the etiology of colon cancer has failed to provide consistent evidence on the role of diet. This may have arisen, in part, from two methodological limitations of the studies: the difficulty of obtaining accurate measurements of diet and the lack of variability in diet among the subjects studied. In case-control studies, diet measurement might be improved if current rather than past diet could be studied and this might be appropriate if studies were based on patients with precursor lesions rather than cancer. Precursor lesions might also serve as endpoints for randomized trials of dietary interventions. In both types of studies, laboratory measurements of specific dietary variables should be used to supplement diet questionnaires. Further, controls should not be selected from patients with diet-related diseases and studies should be conducted in communities with sufficient dietary variability to ensure the presence of an appropriate gradient in risk.


Colonoscopy at a combined district general hospital and specialist endoscopy unit: lessons from 505 consecutive examinations.
Provisional reports from the Intercollegiate British Society of Gastroenterology National Colonoscopy audit show completion rates of 57-77% for the procedure and poor levels of training and supervision. We prospectively audited all aspects of colonoscopy performed at a combined district general hospital and specialist endoscopy unit. Details of referral, examination, endoscopist, complications and follow-up were recorded and patients were sent questionnaires for long-term follow-up. 505 patients (246 male) underwent colonoscopy by 27 different endoscopists. Their median age was 57 years (range 13-92) and 93% were outpatients. 64% patients were symptomatic and 36% were having surveillance or follow-up colonoscopy. The overall caecal intubation rate was 93%, with little difference between surgeons, physicians and experienced trainees (89%, 92%, 94%) and specialist endoscopists (98%). In only one case was an inexperienced trainee (<100 procedures) unsupervised. Pain scores estimated by the endoscopist were well matched with those given by the patient-medians 29 and 26 (maximum 100) respectively. Median satisfaction score was 96 (maximum 100). Polyp pick-up rate was 26.9% and there were 11 new cancers. 16 (3%) minor immediate complications were recorded-5 oversedation, 6 vasovagal attacks, 3 polypectomy haemorrhages and 2 mucosal injuries (neither requiring treatment). 3 patients died within 6 months of follow-up but no death was colonoscopy related. Completion rates in this setting were adequate for all endoscopists studied. Patient satisfaction with the procedure was high and very few immediate or long-term complications were encountered.


Evolution of green plants as deduced from 5S rRNA sequences.
We have constructed a phylogenic tree for green plants by comparing 5S rRNA sequences. The tree suggests that the emergence of most of the uni- and multicellular green algae such as Chlamydomonas, Spirogyra, Ulva, and Chlorella occurred in the early stage of green plant evolution. The branching point of Nitella is a little earlier than that of land plants and much later than that of the above green algae, supporting the view that Nitella-like green algae may be the direct precursor to land plants. The Bryophyta and the Pteridophyta separated from each other after emergence of the Spermatophyta. The result is consistent with the view that the Bryophyta evolved from ferns by degeneration. In the Pteridophyta, Psilotum (whisk fern) separated first, and a little later Lycopodium (club moss) separated from the ancestor common to Equisetum (horsetail) and Dryopteris (fern). This order is in accordance with the classical view. During the Spermatophyta evolution, the gymnosperms (Cycas, Ginkgo, and Metasequoia have been studied here) and the angiosperms (flowering plants) separated, and this was followed by the separation of Metasequoia and Cycas (cycad)/Ginkgo (maidenhair tree) on one branch and various flowering plants on the other.


Hypothalamic oxytocin mediates adaptation mechanism against chronic stress in rats.
Accumulation of continuous life stress (chronic stress) often causes gastric symptoms. Although central oxytocin has antistress effects, the role of central oxytocin in stress-induced gastric dysmotility remains unknown. Solid gastric emptying was measured in rats receiving acute restraint stress, 5 consecutive days of repeated restraint stress (chronic homotypic stress), and 7 consecutive days of varying types of stress (chronic heterotypic stress). Oxytocin and oxytocin receptor antagonist were administered intracerebroventricularly (icv). Expression of corticotropin-releasing factor (CRF) mRNA and oxytocin mRNA in the paraventricular nucleus (PVN) of the hypothalamus was evaluated by real-time RT-PCR. The changes of oxytocinergic neurons in the PVN were evaluated by immunohistochemistry. Acute stress delayed gastric emptying, and the delayed gastric emptying was completely restored after 5 consecutive days of chronic homotypic stress. In contrast, delayed gastric emptying persisted following chronic heterotypic stress. The restored gastric emptying following chronic homotypic stress was antagonized by icv injection of an oxytocin antagonist. Icv injection of oxytocin restored delayed gastric emptying induced by chronic heterotypic stress. CRF mRNA expression, which was significantly increased in response to acute stress and chronic heterotypic stress, returned to the basal levels following chronic homotypic stress. In contrast, oxytocin mRNA expression was significantly increased following chronic homotypic stress. The number of oxytocin-immunoreactive cells was increased following chronic homotypic stress at the magnocellular part of the PVN. Icv injection of oxytocin reduced CRF mRNA expression induced by acute stress and chronic heterotypic stress. It is suggested that the adaptation mechanism to chronic stress may involve the upregulation of oxytocin expression in the hypothalamus, which in turn attenuates CRF expression.


Role of potassium channels in relaxations of canine middle cerebral arteries induced by nitric oxide donors.
The mechanisms underlying smooth muscle relaxations of cerebral arteries in response to nitric oxide (NO) and cyclic GMP (cGMP) are still not completely understood. The present study was designed to determine the role of potassium channels in the relaxations to NO donors 3-morpholinosydnonimine (SIN-1) and sodium nitroprusside (SNP), as well as 8-bromo-3',5' -cGMP (a synthetic analogue of cGMP) and zaprinast (a selective cGMP phosphodiesterase inhibitor). Rings of canine middle cerebral asteries without endothelium were suspended in Krebs-Ringer bicarbonate solution for isometric tension recording. The levels of cGMP were measured by radioimmunoassay. Relaxations to NO donors 8-bromo-cGMP and zaprinast were studied in the presence and in the absence of K+ channel blockers charybdotoxin (large-conductance Ca(2+)-activated K+ channels), glyburide (ATP-sensitive K+ channels), 4-aminopyridine (delayed rectifier K+ channels), and BaCl2 (multiple types of K+ channels). Concentration-dependent relaxations caused by NO donors (SIN-1 and SNP) were significantly reduced in arteries treated with BaCl2 (3 x 10(-4) mol/L) or charybdotoxin (3 x 10(-8) mol/L). Relaxations to 8-bromo-cGMP were not affected by the same concentrations of BaCl2 and charybdotoxin; however, they were reduced by higher concentrations of BaCl2 (3 x 10(-3) mol/L) or charybdotoxin (10(-7) mol/L). Zaprinast-induced relaxations were significantly reduced by BaCl2 (3 x 10(-4) mol/L) or charybdotoxin (3 x 10(-8) mol/L). Glyburide (10(-5) mol/L) and 4-aminopyridine (10(-3) mol/L) did not alter the relaxations to SIN-1 or SNP. The production of cGMP stimulated by SIN-1 in the vascular smooth muscle was not affected by BaCl2 (3 x 10(-3) mol/L) or charybdotoxin (10(-7) mol/L). These results indicate that in canine middle cerebral arteries, a significant portion of relaxations to NO liberated from nitrovasodilators is mediated by large-conductance Ca(2+)-activated K+ channels. Other K+ channels, sensitive to BaCl2, may also be involved in the mechanism of relaxations induced by NO.


Multivariate Extension of Matrix-Based Rényi's α-Order Entropy Functional.
The matrix-based Rényi's α-order entropy functional was recently introduced using the normalized eigenspectrum of a Hermitian matrix of the projected data in a reproducing kernel Hilbert space (RKHS). However, the current theory in the matrix-based Rényi's α-order entropy functional only defines the entropy of a single variable or mutual information between two random variables. In information theory and machine learning communities, one is also frequently interested in multivariate information quantities, such as the multivariate joint entropy and different interactive quantities among multiple variables. In this paper, we first define the matrix-based Rényi's α-order joint entropy among multiple variables. We then show how this definition can ease the estimation of various information quantities that measure the interactions among multiple variables, such as interactive information and total correlation. We finally present an application to feature selection to show how our definition provides a simple yet powerful way to estimate a widely-acknowledged intractable quantity from data. A real example on hyperspectral image (HSI) band selection is also provided.


Horse hooves and bird feathers: Two model systems for studying the structure and development of highly adapted integumentary accessory organs--the role of the dermo-epidermal interface for the micro-architecture of complex epidermal structures.
Accessory organs of the integument are locally modified parts of the potentially feather-bearing skin in birds (e.g., the rhamphotheca, claws, or scales), and of the potentially hairy skin in mammals (e.g., the rhinarium, nails, claws, or hooves). These special parts of the integument are characterised by a modified structure of their epidermal, dermal and subcutaneous layers. The developmental processes of these various integumentary structures in birds and mammals show both similarities and differences. For example, the development of the specialised epidermal structures of both feathers and the hoof capsule is influenced by the local three-dimensional configuration of the dermis. However, in feathers, in contrast to hooves, the arrangement of the corneous cells is only partially a direct result of the particular arrangement and shape of the dermal surface of the papillary body. Whereas the diameter of the feather papilla, as well as the number, length, and width of dermal ridges on the surface of the feather papilla influence the three-dimensional architecture of the feather rami, there is no apparent direct correlation between the dermo-epidermal interface and the development of the highly ordered architecture of the radii and hamuli in the feather vane. In order to elucidate this morphogenic problem and the problem of locally different processes of keratinisation and cornification, the structure and development of feathers in birds are compared to those of the hoof capsule in horses. The equine hoof is the most complex mammalian integumentary structure, which is determined directly by the dermal surface of the papillary body. Perspectives for further research on the development of modified integumentary structures, such as the role of the dermal microangioarchitecture and the selective adhesion and various differentiation pathways of epidermal cells, are discussed.


Current Trends in the Management of Neonates With Ebstein's Anomaly.
The optimal management strategy for neonates with Ebstein's anomaly is unknown. This analysis was undertaken to assess current trends in the management and prognosis of neonates born with Ebstein's anomaly in the United States, as reflected in an administrative database. The Pediatric Health Information System database (40 children's hospitals) was used to review the reported incidence and available data on neonates with Ebstein's anomaly treated in the United States between 2003 and 2007. Primary outcome was hospital survival. Of the 415 patients identified, 257 (62%) did not undergo initial surgical intervention as neonates. Aortopulmonary shunt only was done on 63 patients (15%), single-ventricle palliation on 36 (9%), two-ventricle repair on 16 (4%), heart transplantation in 3 (1%), and a catheter-based intervention or a hybrid palliative approach was applied in 40 (10%). Intergroup comparisons were done using chi-square analyses. Mortality for the entire cohort was 24% (100 of 415). For medically treated patients, this was 22% (56 of 257). For surgically treated and hybrid patients, this was 30% and 23%, respectively (P = NS). The majority of patients born with Ebstein's anomaly currently do not undergo surgical intervention as neonates. Significant early mortality in this group suggests that certain subsets of patients may benefit from earlier surgical intervention. Among the severely symptomatic neonates who do undergo early surgical intervention, the mortality remains high, irrespective of the surgical approach taken. A multicenter trial may be appropriate to identify strategies to optimize care for these critically ill neonates. Further analysis of risk factors for early mortality is warranted.


The "electric" otoplasty.
The goal of otoplasty in the treatment of prominauris is symmetrical restoration of the ears to an aesthetic position with respect to the side of the head. Most commonly, this is accomplished by the creation or enhancement of the antihelical fold. In addition, reduction in the projection of the conchal bowl may be required with manipulation of the antihelical fold. While myriad techniques exist to correct the poorly formed antihelical fold, most involve cartilage weakening and suture placement. Herein we describe a simple and effective technique for cartilage weakening using electrocautery. Using this technique, otoplasty can be performed in a reproducible fashion with a low incidence of complications. In the more than 60 patients treated with this technique, there were no complications related to the use of the electrocautery, and excellent results were consistently obtained.


Clinical teachers' perspectives on cultural competence in medical education.
Globalisation and migration have inevitably shaped the objectives and content of medical education worldwide. Medical educators have responded to the consequent cultural diversity by advocating that future doctors should be culturally competent in caring for patients. As frontline clinical teachers play a key role in interpreting curriculum innovations and implementing both explicit and hidden curricula, this study investigated clinical teachers' attitudes towards cultural competence training in terms of curriculum design, educational effectiveness and barriers to implementation. This study was based on interviews with clinical teachers from university-affiliated hospitals in Taiwan on the subject of cultural competence. The data were transcribed verbatim and translated into English. The interviews were analysed using grounded theory to identify and categorise key themes. Five main themes emerged: (i) there was a clear consensus that students currently lack sufficient cultural competence; (ii) the teachers agreed that increased exposure to cultural diversity improved students' cultural understanding; (iii) present curriculum design was generally agreed to be inadequate, and it was argued that devoting space to developing cultural competence across the curriculum would be a worthwhile endeavour; (iv) different methods of performance assessment were proposed; and (v) the main obstacles to teaching and assessing cultural competence were perceived to be a lack of commonly agreed goals, the low priority accorded to it in an overloaded curriculum and the inadequacy of teachers' cultural competence. Eliciting the viewpoints of the key providers is a first step in curriculum innovation and reform. This study demonstrates that clinical teachers acknowledge the need for explicit and implicit training in cultural competence, but there needs to be further debate about the overall goals of such training, the time allotted to it and how it should be assessed, as well as a faculty-wide development programme addressing pedagogical needs.


Severe form of Cockayne syndrome with varying clinical presentation and no photosensitivity in a family.
We report six patients with Cockayne syndrome type B without photosensitivity. The patients are from the same inbred family and exhibit variable clinical features. The main clinical manifestations were progressive encephalopathy including intracranial calcification and white-matter lesions, dwarfism without growth hormone deficiency, senile appearance, mental and motor retardation, atrophy of subcutaneous fat tissue, severe pectus carinatus, and spasticity. Clinical photosensitivity was not observed in any patient. Other clinical findings were cataract, pigmentary retinopathy, and peripheral neuropathy. The onset of the disease was between 3 and 6 months of age. Molecular genetic analyses in the family established linkage to ERCC6, the gene responsible for Cockayne syndrome type B, confirming the clinical diagnosis.


Precise role of acid in non-erosive reflux disease.
The fundamental abnormality in gastroesophageal reflux disease is exposure of the esophageal epithelium to acidic gastric contents, resulting in histopathologic injury and/or symptoms. With increasing understanding of gastroesophageal reflux disease, non-erosive reflux disease (NERD) is found to account for >50% of cases involving gastroesophageal reflux. There is a good correlation between esophageal acid exposure (EAE) and endoscopic changes. Duration of EAE correlates with severity of erosive esophagitis (EE), and the number of prolonged acid reflux episodes and esophageal exposure to acid and pepsin is increased in more severe reflux. However, there is no convincing evidence to support a significant difference in the acid secretory capacity between patients with NERD or EE. Although acid reflux gives rise to similar symptoms in both NERD and EE patients, the underlying mechanism of acid injury may be different. Dilated intercellular spaces may be responsible for the enhanced perception of proximal acid reflux and dilated intercellular spaces are a feature of NERD patients, irrespective of EAE, and can be considered an objective, structural marker of reflux symptoms. Three different mechanisms have been proposed to explain the occurrence of heartburn in endoscopy-negative patients: esophageal visceral hypersensitivity, sustained esophageal contractions, and abnormal tissue resistance. Impaired esophageal mucosal resistance or increased sensitivity, even to small amounts of acid reflux, plays a key role in the pathophysiology of NERD. Moreover, hyperalgesia may be a predominant mechanism in eliciting symptoms in NERD patients. Increasingly seen are patients with a poor response to acid suppression treatment. Moreover, even double proton pump inhibitor dosing does not completely inhibit gastric acid secretion and relieve all symptoms. Thus, current definitions of acid reflux require review to increase the sensitivity to determine the frequency and implication of short periods of acidity in the esophagus. Analysis such as analysis of the area under the H(+) activity time curve is one alternative approach for evaluating acid secretion. The precise role of acid in NERD needs further clarification.


Sustained exposure to abscisic acid enhances the colonization potential of the mutualist fungus Piriformospora indica on Arabidopsis thaliana roots.
Root colonization by the beneficial fungus Piriformospora indica is controlled by plant innate immunity, but factors that channel this interaction into a mutualistic relationship are not known. We have explored the impact of abscisic acid (ABA) and osmotic stress on the P. indica interaction with Arabidopsis thaliana. The activation of plant innate immunity in roots was determined by measuring the concentration of the phytoalexin camalexin and expression of transcription factors regulating the biosynthesis of tryptophan-related defence metabolites. Furthermore, the impact of the fungus on the content of ABA, salicylic acid, jasmonic acid (JA) and JA-related metabolites was examined. We demonstrated that treatment with exogenous ABA or the ABA analogue pyrabactin increased fungal colonization efficiency without impairment of plant fitness. Concomitantly, ABA-deficient mutants of A. thaliana (aba1-6 and aba2-1) were less colonized, while plants exposed to moderate stress were more colonized than corresponding controls. Sustained exposure to ABA attenuated expression of transcription factors MYB51, MYB122 and WRKY33 in roots upon P. indica challenge or chitin treatment, and prevented an increase in camalexin content. The results indicate that ABA can strengthen the interaction with P. indica as a consequence of its impact on plant innate immunity. Consequently, ABA will be relevant for the establishment and outcome of the symbiosis under stress conditions.


Validation of QUALAS-T, a health-related quality of life instrument for teenagers with spina bifida.
We aimed to develop and validate a self-reported QUAlity of Life Assessment in Spina bifida for Teenagers (QUALAS-T). We drafted a 46-question pilot instrument using a patient-centered comprehensive item generation/refinement process. A group of 13-17 years olds with spina bifida (SB) was recruited online via social media and in person at SB clinics (2013-2015). Healthy controls were recruited during routine pediatrician visits. Final questions were identified based on clinical relevance, factor analysis and domain psychometrics. Teenagers with SB completed the validated generic Kidscreen-27 instrument. Median age of 159 participants was 15.2 years (42.0% male, 77.4% Caucasian), similar to 58 controls (p ≥ 0.06). There were 102 online and 57 clinic participants (82.8% of eligible). Patients, parents and an expert panel established face and content validity of the 2-domain, 10-question QUALAS-T. Internal consistency and test-retest reliability were high for the Family and Independence and Bladder and Bowel domains (Cronbach's alpha: 0.76-0.78, ICC: 0.72-0.75). The Bladder and Bowel domain is the same for QUALAS-T , QUALAS-A for adults and QUALAS-C for children. Correlations between QUALAS-T domains were low (r = 0.34), indicating QUALAS-T can differentiate between distinct HRQOL components. Correlations between QUALAS-T and Kidscreen-27 were also low (r ≤0.41). QUALAS-T scores were lower in teenagers with SB than without (p <0.0001). QUALAS-T is a short, valid HRQOL tool for adolescents with SB, applicable in clinical and research settings. Since the Bladder & Bowel domains for all QUALAS versions are the same, Bladder and Bowel HRQOL can be measured on the same scale from age 8 through adulthood.


Suspected caffeine and ephedrine toxicosis resulting from ingestion of an herbal supplement containing guarana and ma huang in dogs: 47 cases (1997-1999).
To describe the clinical signs following ingestion of an herbal supplement containing guarana and ma huang in dogs, estimate minimum dose at which clinical signs of toxicosis and death were reported, and evaluate treatment options. Retrospective study. 47 dogs with evidence of ingestion of an herbal supplement containing primarily guarana and ma huang. Records of dogs that had ingested an herbal supplement containing ma huang and guarana between July 1997 and October 1999 were retrieved from the National Animal Poison Control Center database. Data were retrieved and reviewed regarding signalment, dose ingested, clinical signs, laboratory test results, treatment, and final outcome. Cases were assessed by staff veterinarians as toxicosis or suspected toxicosis on the basis of strength of evidence supporting a diagnosis. Most dogs (80%) developed clinical signs of toxicosis within 8 hours of ingestion, and clinical signs persisted for up to 48 hours. Hyperactivity, tremors, seizures, and behavior changes were reported in 83% of dogs; other signs included vomiting (47%), tachycardia (30%), and hyperthermia (28%). Seventeen percent of the dogs died or were euthanatized. Estimated doses of guarana and ma huang ranged from 4.4 to 296.2 mg/kg (1.98 to 133.2 mg/lb) and 1.3 to 88.9 mg/kg (0.58 to 40.0 mg/lb) of body weight, respectively; minimum dose at which death was reported was 19.1 mg of guarana/kg (8.7 mg/lb) and 5.8 mg of ma huang/kg (2.6 mg/lb). Accidental ingestion of herbal supplements containing primarily guarana and ma huang in dogs can lead to a potentially lethal condition that may require prompt detoxification and supportive treatment for several days. Most dogs recovered with supportive treatment.


Neuronal microRNA deregulation in response to Alzheimer's disease amyloid-beta.
Normal brain development and function depends on microRNA (miRNA) networks to fine tune the balance between the transcriptome and proteome of the cell. These small non-coding RNA regulators are highly enriched in brain where they play key roles in neuronal development, plasticity and disease. In neurodegenerative disorders such as Alzheimer's disease (AD), brain miRNA profiles are altered; thus miRNA dysfunction could be both a cause and a consequence of disease. Our study dissects the complexity of human AD pathology, and addresses the hypothesis that amyloid-beta (Abeta) itself, a known causative factor of AD, causes neuronal miRNA deregulation, which could contribute to the pathomechanisms of AD. We used sensitive TaqMan low density miRNA arrays (TLDA) on murine primary hippocampal cultures to show that about half of all miRNAs tested were down-regulated in response to Abeta peptides. Time-course assays of neuronal Abeta treatments show that Abeta is in fact a powerful regulator of miRNA levels as the response of certain mature miRNAs is extremely rapid. Bioinformatic analysis predicts that the deregulated miRNAs are likely to affect target genes present in prominent neuronal pathways known to be disrupted in AD. Remarkably, we also found that the miRNA deregulation in hippocampal cultures was paralleled in vivo by a deregulation in the hippocampus of Abeta42-depositing APP23 mice, at the onset of Abeta plaque formation. In addition, the miRNA deregulation in hippocampal cultures and APP23 hippocampus overlaps with those obtained in human AD studies. Taken together, our findings suggest that neuronal miRNA deregulation in response to an insult by Abeta may be an important factor contributing to the cascade of events leading to AD.


Modelling biomechanical requirements of a rider for different horse-riding techniques at trot.
The simplest model possible for bouncing systems consists of a point mass bouncing passively on a mass-less spring without viscous losses. This type of spring-mass model has been used to describe the stance period of symmetric running gaits. In this study, we investigated the interaction between horse and rider at trot using three models of force-driven spring (-damper)-mass systems. The first system consisted of a spring and a mass representing the horse that interact with another spring and mass representing the rider. In the second spring-damper-mass model, dampers, a free-fall and a forcing function for the rider were incorporated. In the third spring-damper-mass model, an active spring system for the leg of the rider was introduced with a variable spring stiffness and resting length in addition to a saddle spring with fixed material properties. The output of the models was compared with experimental data of sitting and rising trot and with the modern riding technique used by jockeys in racing. The models show which combinations of rider mass, spring stiffness and damping coefficient will result in a particular riding technique or other behaviours. Minimization of the peak force of the rider and the work of the horse resulted in an 'extreme' modern jockey technique. The incorporation of an active spring system for the leg of the rider was needed to simulate rising trot. Thus, the models provide insight into the biomechanical requirements a rider has to comply with to respond effectively to the movements of a horse.


Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction.
The mechanisms that mediate the tightly controlled production and clearance of glucose during muscular work are unclear, and it has been suggested that an unidentified "work factor" exists that influences the contraction-induced increase in endogenous glucose production (EGP). The cytokine interleukin (IL)-6 is released from skeletal muscle during contraction. Here we show that IL-6 contributes to the contraction-induced increase in EGP. Six men performed 2 h of bicycle exercise on three separate occasions, at a relatively high intensity (HI) or at a low intensity with (LO + IL-6) or without (LO) an infusion of recombinant human IL-6 that matched the circulating concentration of IL-6 seen in HI exercise. The stable isotope 6,6 (2)H(2) glucose was infused to calculate EGP (rate of glucose appearance [R(a)]), whole-body glucose disposal (rate of glucose disappearance [R(d)]), and metabolic clearance rate (MCR) of glucose. Glucose R(a), R(d), and MCR were higher (P < 0.05) at HI than at LO. Throughout exercise at LO + IL-6, glucose R(a) and R(d) were higher (P < 0.05) than LO, even though the exercise intensity was identical. In addition, MCR was higher (P < 0.05) at LO + IL-6 than at LO at 90 min. Insulin, glucagon, epinephrine, norepinephrine, cortisol, and growth hormone were identical when comparing LO + IL-6 with LO. These data suggest that IL-6 influences glucose homeostasis during exercise. Our results provide potential new insights into factors that mediate glucose production and disposal and implicates IL-6 in the so-called "work factor."


Impact of artemisinin-based combination therapy and insecticide-treated nets on malaria burden in Zanzibar.
The Roll Back Malaria strategy recommends a combination of interventions for malaria control. Zanzibar implemented artemisinin-based combination therapy (ACT) for uncomplicated malaria in late 2003 and long-lasting insecticidal nets (LLINs) from early 2006. ACT is provided free of charge to all malaria patients, while LLINs are distributed free to children under age 5 y ("under five") and pregnant women. We investigated temporal trends in Plasmodium falciparum prevalence and malaria-related health parameters following the implementation of these two malaria control interventions in Zanzibar. Cross-sectional clinical and parasitological surveys in children under the age of 14 y were conducted in North A District in May 2003, 2005, and 2006. Survey data were analyzed in a logistic regression model and adjusted for complex sampling design and potential confounders. Records from all 13 public health facilities in North A District were analyzed for malaria-related outpatient visits and admissions. Mortality and demographic data were obtained from District Commissioner's Office. P. falciparum prevalence decreased in children under five between 2003 and 2006; using 2003 as the reference year, odds ratios (ORs) and 95% confidence intervals (CIs) were, for 2005, 0.55 (0.28-1.08), and for 2006, 0.03 (0.00-0.27); p for trend < 0.001. Between 2002 and 2005 crude under-five, infant (under age 1 y), and child (aged 1-4 y) mortality decreased by 52%, 33%, and 71%, respectively. Similarly, malaria-related admissions, blood transfusions, and malaria-attributed mortality decreased significantly by 77%, 67% and 75%, respectively, between 2002 and 2005 in children under five. Climatic conditions favorable for malaria transmission persisted throughout the observational period. Following deployment of ACT in Zanzibar 2003, malaria-associated morbidity and mortality decreased dramatically within two years. Additional distribution of LLINs in early 2006 resulted in a 10-fold reduction of malaria parasite prevalence. The results indicate that the Millennium Development Goals of reducing mortality in children under five and alleviating the burden of malaria are achievable in tropical Africa with high coverage of combined malaria control interventions.


Nanomedicine-Enabled Chemical Regulation of Reactive X Species for Versatile Disease Treatments.
Reactive X species (RXS), encompassing elements such as O, N, C, S, Se, Cl, Br, I, and H, play vital roles in cell biology and physiological function, impacting cellular signal transduction, metabolic regulation, and disease processes. The redox unbalance of RXS is firmly implicated in an assortment of physiological and pathological disorders, including cancer, diabetes, cardiovascular disease, and neurodegenerative diseases. However, the intricate nature and multifactorial dependence of RXS pose challenges in comprehending and precisely modulating their biological behavior. Nanomaterials with distinct characteristics and biofunctions offer promising avenues for generating or scavenging RXS to maintain redox homeostasis and advance disease therapy. This minireview provides a tutorial summary of the relevant chemistry and specific mechanisms governing different RXS, focusing on cellular metabolic regulation, stress responses, and the role of nanomedicine in RXS generation and elimination. The challenges associated with chemically regulating RXS for diverse disease treatments are further discussed along with the future prospects, aiming to facilitate the clinical translation of RXS-based nanomedicine and open new avenues for improved therapeutic interventions.


Protein cross-linking, peroxidase and beta-1,3-endoglucanase involved in resistance of pea against Orobanche crenata.
Root holoparasitic angiosperms, like Orobanche spp, completely lack chlorophyll and totally depend on their host for their supply of nutrients. O. crenata is a severe constraint to the cultivation of legumes and breeding for resistance remains the most economical, feasible, and environmentally friendly method of control. Due to the lack of resistance in commercial pea cultivars, the use of wild relatives for breeding is necessary, and an understanding of the mechanisms underlying host resistance is needed in order to improve screening for resistance in breeding programmes. Compatible and incompatible interactions between O. crenata and pea have been studied using cytochemical procedures. The parasite was stopped in the host cortex before reaching the central cylinder, and accumulation of H2O2, peroxidases, and callose were detected in neighbouring cells. Protein cross-linking in the host cell walls appears as the mechanism of defence, halting penetration of the parasite. In situ hybridization studies have also shown that a peroxidase and a beta-glucanase are differently expressed in cells of the resistant host (Pf651) near the penetration point. The role of these proteins in the resistance to O. crenata is discussed.


Identification of serological biomarker profiles associated with total joint replacement in osteoarthritis patients.
Establish a biomarker panel associated with all-cause total joint replacement (TJR) through identification of patients with osteoarthritis (OA) who do or do not progress to TJR and investigate effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Serum samples from patients enrolled in phase III trials of tanezumab who experienced TJR (n = 174) or matched patients who did not (n = 321) were analyzed for bone, cartilage, soft tissue, and inflammation markers. Classification and Regression Tree (CART) analysis was used to identify biomarker phenotypes associated with TJR. At baseline, biomarker combinations for patients who did not use NSAIDs before starting tanezumab and used NSAIDs during tanezumab treatment <90 days ("nonNSAID"), identified 77% (95% confidence interval [CI]: 71-84%) of patients who experienced TJR and 77% (95% CI: 65-86%) who did not over a 6-month study period (on average). These biomarker combinations increased odds of identifying patients to remain free of a TJR by 3.3-fold. In patients who used NSAIDs continuously (during screening and ≥90 days during tanezumab treatment), 64% (95% CI: 54-73%) who had TJR and 75% (95% CI: 68-83%) who did not were identified by biomarker combinations different from nonNSAID patients, with an increase in odds of identifying patients to remain free of a TJR by two-fold. Although validation on other cohorts is necessary, biomarkers may assist in identifying patients who will need TJR. The profiles suggest NSAID use increases importance of bone metabolism in TJR pathology.


Cognitive function in patients with stable coronary heart disease: Related cerebrovascular and cardiovascular responses.
Chronic exercise has been shown to prevent or slow age-related decline in cognitive functions in otherwise healthy, asymptomatic individuals. We sought to assess cognitive function in a stable coronary heart disease (CHD) sample and its relationship to cerebral oxygenation-perfusion, cardiac hemodynamic responses, and [Formula: see text] peak compared to age-matched and young healthy control subjects. Twenty-two young healthy controls (YHC), 20 age-matched old healthy controls (OHC) and 25 patients with stable CHD were recruited. Cognitive function assessment included short term-working memory, perceptual abilities, processing speed, cognitive inhibition and flexibility and long-term verbal memory. Maximal cardiopulmonary function (gas exchange analysis), cardiac hemodynamic (impedance cardiography) and left frontal cerebral oxygenation-perfusion (near-infra red spectroscopy) were measured during and after a maximal incremental ergocycle test. Compared to OHC and CHD, YHC had higher [Formula: see text] peak, maximal cardiac index (CI max), cerebral oxygenation-perfusion (ΔO2 Hb, ΔtHb: exercise and recovery) and cognitive function (for all items) (P<0.05). Compared to OHC, CHD patients had lower [Formula: see text] peak, CI max, cerebral oxygenation-perfusion (during recovery) and short term-working memory, processing speed, cognitive inhibition and flexibility and long-term verbal memory (P<0.05). [Formula: see text] peak and CI max were related to exercise cerebral oxygenation-perfusion and cognitive function (P<0.005). Cerebral oxygenation-perfusion (exercise) was related to cognitive function (P<0.005). Stable CHD patients have a worse cognitive function, a similar cerebral oxygenation/perfusion during exercise but reduced one during recovery vs. their aged-matched healthy counterparts. In the all sample, cognitive functions correlated with [Formula: see text] peak, CI max and cerebral oxygenation-perfusion.


Self-Etch Adhesive as a Carrier for ACP Nanoprecursors to Deliver Biomimetic Remineralization.
Lab biomineralization should be carried out in an actual clinical practice. This study evaluated self-etch adhesive as a carrier for amorphous calcium phosphate (ACP) nanoprecursors to continuously deliver biomimetic remineralization of self-assembly type I collagen and demineralized dentin. Si-containing ACP particles (Si-ACP) stabilized with polyaspartic acid (PAsp) were synthesized and characterized by transmission electron microscopy (TEM), scanning electron microscopy-energy-dispersive X-ray spectroscopy, Fourier transform infrared analysis, X-ray powder diffractometry, and X-ray phototelectron spectroscopy. The biomimetic remineralization of single-layer reconstituted type I collagen fibrils and demineralized dentin was analyzed by using two one-bottle self-etch dentin adhesives (Clearfil S3 Bond (S3), Kurraray-Noritake; Adper Easy One (AEO), 3 M ESPE) as a carrier loaded (or not, in the case of the control) with 25 wt % of Si-ACP particles. In vitro cytotoxicity assessed by the Cell Counting Kit-8 indicated that the Si-ACP particles had no adverse effect on cell viability. The capacity for Ca and P ions release from cured Si-ACP-containing adhesives (S3, AEO) was evaluated by inductively coupled plasma-atomic emission spectrometry, revealing the successively increasing release of Ca and P ions for 28 days. The intra- and extrafibrillar remineralization of type I collagen and demineralized dentin was confirmed by TEM and selected-area electron diffraction when the adhesives were used as a carrier loaded with Si-ACP particles. Therefore, we propose self-etch adhesive as a novel carrier for ACP nanoprecursors to continuously deliver biomimetic remineralization.


CT venography and pathological characterization of crus haemorrhage in Pekin ducks.
The crus haemorrhage is one of the main causes of carcass defects in Pekin duck processing houses. However, its pathologic features are currently unclear. In order to examine the injury to the hind limb veins and illustrate the pathologic characteristics of crus haemorrhage in Pekin ducks, a total of 68 Pekin ducks with crus haemorrhage (test group) and 10 unaffected ducks (control group) were collected in this study. Five ducks randomly selected from each group were examined by computed tomographic venography with 2.0 mm thickness, 120 kVp, and 90 mA. Pathological changes were observed macroscopically, and under a microscope and electron microscope. The computed tomographic venography results showed no differences in the main hind limb veins between Pekin ducks with crus haemorrhage and the control. Macroscopic results demonstrated that the haemorrhage only occurred in crural muscles, most frequently in musculus gastrocnemius and musculus tibialis cranialis. In severe cases, muscular rupture and multiple intermuscular blood clots could be observed. Histological analysis showed rupture of myofibers and massive red blood cells between muscle bundles. Besides, infiltration of connective tissues and inflammatory lesions could be seen. However, no differences were observed in other organs between these two groups. The main ultrastructural characteristics were myofibrillar rupture and split, accompanied by mitochondrial membrane disintegration and vacuolization. All these results indicate that the haemorrhage in crus is a focal myopathy with the characteristics of bleeding, rupture, and inflammatory lesions. Research highlights CTV was a feasible method to evaluate the hind limb veins in Pekin ducks. The focal myopathy presented here only affected crural muscles. The focal myopathy was characterized by bleeding, rupture and inflammatory lesions.


Exploring the Spatiotemporal Evolution and Sustainable Driving Factors of Information Flow Network: A Public Search Attention Perspective.
The promotion of information flow reinforces the interactive cooperation and evolutionary process among cities. In the information age, public online search is a typical behavior of Internet society, which is the key to information flow generation and agglomeration. In this study, we attempt to explore the evolutionary characteristics of intercity networks driven by public online social behavior in the information age and construct an information flow network (IFN) from the perspective of public search attention. We also explore the evolution of the IFN in terms of the whole network, node hierarchy, and subgroup aggregation. Meanwhile, we also discuss the impact of the sustainable driving factors on the IFN. Finally, an empirical study was conducted in Guanzhong Plain Urban Agglomeration (GPUA). Our results show that: (1) the information flow in GPUA fluctuating upward in the early study period and gradually decreasing in the later study period. However, the agglomeration degree of information flow in the urban agglomeration continues to increase. (2) The hierarchical structure of urban nodes in GPUA presents a trend of "high in the middle and low on both sides", and the formation of subgroups is closely related to geographic location. (3) The driving factors all impacting the IFN include public ecology, resource investment, information infrastructure, and economic foundation. This study provides theoretical and practical support for exploring the intercity network and promotes the sustainable urban development.


Prognostic performance of metabolic indexes in predicting onset of type 1 diabetes.
In this investigation we evaluated nine metabolic indexes from intravenous glucose tolerance tests (IVGTTs) and oral glucose tolerance tests (OGTTs) in an effort to determine their prognostic performance in predicting the development of type 1 diabetes in those with moderate risk, as defined by familial relation to a type 1 diabetic individual, a positive test for islet cell antibodies and insulin autoantibody, but normal glucose tolerance. Subjects (n = 186) who had a projected risk of 25-50% for developing type 1 diabetes within 5 years were followed until clinical diabetes onset or the end of the study as part of the Diabetes Prevention Trial-Type 1. Prognostic performance of the metabolic indexes was determined using receiver operating characteristic (ROC) curve and survival analyses. Two-hour glucose from an OGTT most accurately predicted progression to disease compared with all other metabolic indicators with an area under the ROC curve of 0.67 (95% CI 0.59-0.76), closely followed by the ratio of first-phase insulin response (FPIR) to homeostasis model assessment of insulin resistance (HOMA-IR) with an area under the curve value of 0.66. The optimal cutoff value for 2-h glucose (114 mg/dl) maintained sensitivity and specificity values >0.60. The hazard ratio for those with 2-h glucose ≥ 114 mg/dl compared with those with 2-h glucose <114 mg/dl was 2.96 (1.67-5.22). The ratio of FPIR to HOMA-IR from an IVGTT provided accuracy in predicting the development of type 1 diabetes similar to that of 2-h glucose from an OGTT, which, because of its lower cost, is preferred. The optimal cutoff value determined for 2-h glucose provides additional guidance for clinicians to identify subjects for potential prevention treatments before the onset of impaired glucose tolerance.


Ethical problems in ex vivo or cadaver organ transplantation: should the donation be paid?
Financial incentives for organ donation (from living or cadaveric donors) have been considered ethically acceptable by some bioethicists, and recently, according to the media, by Prof. Gary Becker, Nobel Laureate for Economy. However, the only countries to have approved a law allowing financial incentives for organ donation are Iran in 1988 and, in some way and much later, Singapore and Saudi Arabia. In Europe financial incentives for donors are prohibited, except maybe in Austria. In Germany, it is forbidden to purchase organs not only in the home country, but all over the world. The author was involved, as peer reviewer of a major international Transplant journal, in the evaluation of some papers concerning paid kidney living donors in Iran, and therefore made an extensive literature search on this topic and more generally on paid kidney living donation all over the world. The situation in Italy will also be reported and analysed.


Prevalence and diffusion of helmet use at ski areas in Western North America in 2001-02.
The purpose of this study was to examine diffusion of and predictors of helmet use among skiers and snowboarders in the Western United States and Canada. 6400 skiers and snowboarders at 29 ski resorts in the Western United States and Canada were interviewed on chair lifts and observed for helmet use during two consecutive ski seasons (winters 2001 and 2002). Skiers and snowboarders were observed and interviewed at 29 ski resorts in Alaska, California, Colorado, Idaho, Montana, New Mexico, Nevada, Oregon, Utah, and British Columbia as part of a sun protection project. Participants completing the survey consisted of 3525 adult skiers and snowboarders in the 2002 season and 2978 adult skiers and snowboarders in the 2001 season. The outcome measure for all analyses was prevalence of helmet use by skiers and snowboarders. Helmet use by skiers and snowboarders is increasing and is most prevalent among snowboarders, experts, and more frequent skiers/snowboarders. No evidence was found for the hypothesis that helmet use is diffusing more rapidly among earlier adopters of helmets than later adopters. Although controversy remains, helmets are rapidly diffusing as a safety device at western North American ski resorts. Expert and more frequent skiers and snowboarders are more likely to wear helmets, which may indicate that helmets are recognized as a safety device.


Challenging the state of the art in protein structure prediction: Highlights of experimental target structures for the 10th Critical Assessment of Techniques for Protein Structure Prediction Experiment CASP10.
For the last two decades, CASP has assessed the state of the art in techniques for protein structure prediction and identified areas which required further development. CASP would not have been possible without the prediction targets provided by the experimental structural biology community. In the latest experiment, CASP10, more than 100 structures were suggested as prediction targets, some of which appeared to be extraordinarily difficult for modeling. In this article, authors of some of the most challenging targets discuss which specific scientific question motivated the experimental structure determination of the target protein, which structural features were especially interesting from a structural or functional perspective, and to what extent these features were correctly reproduced in the predictions submitted to CASP10. Specifically, the following targets will be presented: the acid-gated urea channel, a difficult to predict transmembrane protein from the important human pathogen Helicobacter pylori; the structure of human interleukin (IL)-34, a recently discovered helical cytokine; the structure of a functionally uncharacterized enzyme OrfY from Thermoproteus tenax formed by a gene duplication and a novel fold; an ORFan domain of mimivirus sulfhydryl oxidase R596; the fiber protein gene product 17 from bacteriophage T7; the bacteriophage CBA-120 tailspike protein; a virus coat protein from metagenomic samples of the marine environment; and finally, an unprecedented class of structure prediction targets based on engineered disulfide-rich small proteins.


De-politicizing parasites: reflections on attempts to control the control of neglected tropical diseases.
Large amounts of funding are being allocated to the control of neglected tropical diseases. Strategies primarily rely on the mass distribution of drugs to adults and children living in endemic areas. The approach is presented as morally appropriate, technically effective, and context-free. Drawing on research undertaken in East Africa, we discuss ways in which normative ideas about global health programs are used to set aside social and biological evidence. In particular, there is a tendency to ignore local details, including information about actual drug take up. Ferguson's 'anti-politics' thesis is a useful starting point for analyzing why this happens, but is overly deterministic. Anti-politics discourse about healing the suffering poor may shape thinking and help explain cognitive dissonance. However, use of such discourse is also a means of strategically promoting vested interests and securing funding. Whatever the underlying motivations, rhetoric and realities are conflated, with potentially counterproductive consequences.


Efficiency of a bagasse substrate in a biological bed system for the degradation of glyphosate, malathion and lambda-cyhalothrin under tropical climate conditions.
After the rinsing of spray equipment, the rinsing water contains polluting products. One way to avoid pollution is to bring the rinsing water over a purification system, a biological bed. The system consists of an impermeable tub filled with a biomix substrate that facilitates biodegradation of pesticides. Usually, straw is one component of the biomix. The objective of this study was to assess the efficiency of an unusual substrate, bagasse, a residue of sugar cane, for the degradation of three pesticides, glyphosate, malathion and lambda-cyhalothrin. Results showed that more than 99% of malathion and glyphosate were degraded in 6 months. In the biological bed, the DT(50) value for malathion was 17 days, for glyphosate 33 days and for lambda-cyhalothrin 43 days. The degradation rate of aminomethylphosphonic acid (AMPA) residues from the degradation of glyphosate was slower than that of the other pesticides (DT(50) 69 days). Finally, the innocuousness of the biomix after 6 months of degradation was confirmed by biological tests. Although the degradation rates of the three pesticides in the present bagasse-based system were similar to those under temperate conditions, the degradation conditions were improved by comparison with those in soil under the given tropical conditions. Further benefits of this system are pesticide confinement, to avoid their dispersion in the environment by liquids or solids, and a lower overall cost. Finally, possibilities for optimising the bagasse-based system (e.g. management of the water content and nature of the biomix) are discussed.


The role of ischemic preconditioning in the expression of apoptosis-related genes in a rat model of intestinal ischemia-reperfusion injury.
To analyze the effects of ischemic preconditioning (IPC) in the expression of apoptosis-related genes in rat small intestine subjected to ischemia and reperfusion. Thirty anesthetized rats underwent laparotomy and were drive into five groups: control (CG); ischemia (IG); ischemia and reperfusion (IRG); IPC and ischemia (IG+IPC); IPC and ischemia and reperfusion (I/RG+IPC). Intestinal ischemia was performed by clamping the superior mesenteric artery for 60 minutes, whereas reperfusion lasted for 120 minutes. IPC was carried out by one cycle of 5 minutes of ischemia followed by 10 minutes of reperfusion prior to the prolonged 60-minutes-ischemia and 120-minutes-reperfusion. Thereafter, the rats were euthanized and samples of small intestine were processed for histology and gene expression. Histology of myenteric plexus showed a higher presence of neurons presenting pyknotic nuclei and condensed chromatin in the IG and IRG. IG+IPC and I/RG+IPC groups exhibited neurons with preserved volume and nuclei, along with significant up-regulation of the anti-apoptotic protein Bcl2l1 and down-regulation of pro-apoptotic genes. Moreover, Bax/Bcl2 ratio was lower in the groups subjected to IPC, indicating a protective effect of IPC against apoptosis. Ischemic preconditioning protect rat small intestine against ischemia/reperfusion injury, reducing morphologic lesions and apoptosis.


Analysis of the beta-glucoside utilization (bgl) genes of Shigella sonnei: evolutionary implications for their maintenance in a cryptic state.
The pattern of expression of the genes involved in the utilization of aryl beta-glucosides such as arbutin and salicin is different in the genus Shigella compared to Escherichia coli. The results presented here indicate that the homologue of the cryptic bgl operon of E. coli is conserved in Shigella sonnei and is the primary system involved in beta-glucoside utilization in the organism. The organization of the bgl genes in S. sonnei is similar to that of E. coli; however there are three major differences in terms of their pattern of expression. (i) The bglB gene, encoding phospho-beta-glucosidase B, is insertionally inactivated in S. sonnei. As a result, mutational activation of the silent bgl promoter confers an Arbutin-positive (Arb(+)) phenotype to the cells in a single step; however, acquiring a Salicin-positive (Sal(+)) phenotype requires the reversion or suppression of the bglB mutation in addition. (ii) Unlike in E. coli, a majority of the activating mutations (conferring the Arb(+) phenotype) map within the unlinked hns locus, whereas activation of the E. coli bgl operon under the same conditions is predominantly due to insertions within the bglR locus. (iii) Although the bgl promoter is silent in the wild-type strain of S. sonnei (as in the case of E. coli), transcriptional and functional analyses indicated a higher basal level of transcription of the downstream genes. This was correlated with a 1 bp deletion within the putative Rho-independent terminator present in the leader sequence preceding the homologue of the bglG gene. The possible evolutionary implications of these differences for the maintenance of the genes in the cryptic state are discussed.


Estrogen-progestin replacement therapy and endometrial cancer.
It has been known for more than 20 years that estrogen replacement therapy substantially increases a woman's risk of developing endometrial cancer. To reduce this increased risk, progestins have been added to estrogen replacement therapy for between 5 and 15 days (usually 7 or 10 days) per "month" in a sequential fashion (sequential estrogen-progestin replacement therapy) or with each dose of estrogen replacement therapy (continuous combined replacement therapy). At the present time, however, little is known about the effects of varying the number of days that progestin is used in sequential estrogen-progestin replacement therapy. We sought to determine the effects of sequential estrogen-progestin replacement therapy and continuous combined replacement therapy on a woman's risk of developing endometrial cancer. A population-based, case-control study of 833 case subjects and 791 control subjects was conducted. Women were postmenopausal, white, and aged 50-74 years when first diagnosed with invasive endometrial cancer or were aged 50-74 years at the matching date for control subjects. All subjects were interviewed in person with the aid of a month-by-month calendar. Relative risks were estimated by odds ratios (ORs); ORs were adjusted simultaneously for the different forms of hormone replacement therapy and for the known endometrial cancer risk factors. The adjusted OR was 2.17 (95% confidence interval [CI] = 1.91-2.47) per 5 years of estrogen replacement therapy use (based on 422 users among the case subjects and 262 users among the control subjects). For women who received sequential estrogen-progestin replacement therapy with the progestin given for less than 10 days (effectively 7 days) per month, the adjusted OR was only slightly reduced to 1.87 (95% CI = 1.32-2.65) per 5 years of use (74 case subjects and 47 control subjects). However, when progestin was given for 10 or more days (effectively 10 days), there was essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.82-1.41) (79 case subjects and 88 control subjects). Continuous combined replacement therapy was also associated with essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.80-1.43) (94 case subjects and 81 control subjects). The progestin in sequential estrogen-progestin replacement therapy needs to be given for at least 10 days to block effectively any increased risk of endometrial cancer. Continuous combined estrogen-progestin therapy is similarly effective. Neither regimen reduces a woman's underlying risk of endometrial cancer. The sharp distinction between the effects of less than 10 days (effectively 7 days) and 10 or more days (effectively 10 days) of progestin use in sequential estrogen-progestin replacement therapy suggests that the extent of endometrial sloughing may play a critical role in determining endometrial cancer risk.


Low yield of bacterial stool culture in children with nosocomial diarrhea.
To determine whether bacterial stool cultures (BSC) are useful in initial evaluation of children with symptoms of nosocomial diarrhea. To answer this question we performed a retrospective record review to determine the yield of BSC in children who developed diarrhea after the third hospital day (HD-3). The hospital computer record keeping system was utilized to compile the result of BSC collected from children and adolescents ages 0 to 20 years between January 1, 1988, and October 31, 1996. All specimens were analyzed for Salmonella, Shigella, Yersinia and Campylobacter. We reviewed hospital charts of all children who developed a positive BSC beyond HD-3 to determine the time of onset of diarrhea and clinical circumstances. A total of 11 516 BSCs were submitted from 9262 children during the 8 1/2-year period. Five hundred sixty-eight (6.6%) of 9262 children had at least 1 positive BSC. Two thousand five hundred seventy-two children had the first BSC submitted after HD-3 and 13 (0.5%) of these children had a positive result. Chart review of these 13 children demonstrated that 6 had onset of diarrhea during the first 3 hospital days. Therefore only 7 children met our criteria for having nosocomially acquired diarrhea caused by a bacterial pathogen. Children whose first BSC was submitted after HD-3 accounted for 3767 (46%) of the total 8126 inpatient BSCs and in excess of $21000 annually in patient billing charges. In the absence of a known exposure the isolation of a bacterial pathogen from the stool of children with onset of diarrhea beyond HD-3 is a rare event. Under most circumstances BSC should not be part of the initial evaluation of children with symptoms of nosocomial diarrhea.


CRISPR-Cas9 Structures and Mechanisms.
Many bacterial clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) systems employ the dual RNA-guided DNA endonuclease Cas9 to defend against invading phages and conjugative plasmids by introducing site-specific double-stranded breaks in target DNA. Target recognition strictly requires the presence of a short protospacer adjacent motif (PAM) flanking the target site, and subsequent R-loop formation and strand scission are driven by complementary base pairing between the guide RNA and target DNA, Cas9-DNA interactions, and associated conformational changes. The use of CRISPR-Cas9 as an RNA-programmable DNA targeting and editing platform is simplified by a synthetic single-guide RNA (sgRNA) mimicking the natural dual trans-activating CRISPR RNA (tracrRNA)-CRISPR RNA (crRNA) structure. This review aims to provide an in-depth mechanistic and structural understanding of Cas9-mediated RNA-guided DNA targeting and cleavage. Molecular insights from biochemical and structural studies provide a framework for rational engineering aimed at altering catalytic function, guide RNA specificity, and PAM requirements and reducing off-target activity for the development of Cas9-based therapies against genetic diseases.


Evaluation of convolutional neural network for recognizing uterine contractions with electrohysterogram.
Uterine contraction (UC) activity is commonly used to monitor the approach of labour and delivery. Electrohysterograms (EHGs) have recently been used to monitor UC and distinguish between efficient and inefficient contractions. In this study, we aimed to identify UC in EHG signals using a convolutional neural network (CNN). An open-access database (Icelandic 16-electrode EHG database from 45 pregnant women with 122 recordings, DB1) was used to develop a CNN model, and 14000 segments with a length of 45 s (7000 from UCs and 7000 from non-UCs, which were determined with reference to the simultaneously recorded tocography signals) were manually extracted from the 122 EHG recordings. Five-fold cross-validation was applied to evaluate the ability of the CNN to identify UC based on its sensitivity (SE), specificity (SP), accuracy (ACC), and area under the receiver operating characteristic curve (AUC). The CNN model developed using DB1 was then applied to an independent clinical database (DB2) to further test its generalisation for recognizing UCs. The EHG signals in DB2 were recorded from 20 pregnant women using our multi-channel system, and 308 segments (154 from UCs and 154 from non-UCs) were extracted. The CNN model from five-fold cross-validation achieved average SE, SP, ACC, and AUC of 0.87, 0.98, 0.93, and 0.92 for DB1, and 0.88, 0.97, 0.93, and 0.87 for DB2, respectively. In summary, we demonstrated that CNN could effectively identify UCs using EHG signals and could be used as a tool for monitoring maternal and foetal health.


Deep sub-wavelength localization of light and sound in dielectric resonators.
Optomechanical crystals provide coupling between phonons and photons by confining them to commensurate wavelength-scale dimensions. We present a new concept for designing optomechanical crystals capable of achieving unprecedented coupling rates by confining optical and mechanical waves to deep sub-wavelength dimensions. Our design is based on a dielectric bowtie unit cell with an effective optical/mechanical mode volume of 7.6 × 10-3(λ/nSi)3/1.2×10-3 λ mech 3. We present results from numerical modeling, indicating a single-photon optomechanical coupling of 2.2 MHz with experimentally viable parameters. Monte Carlo simulations are used to demonstrate the design's robustness against fabrication disorder.


Derivation and validation of diagnostic models for myocardial fibrosis in duchenne muscular dystrophy: assessed by multi-parameter cardiovascular magnetic resonance.
Gadolinium-enhanced cardiovascular magnetic resonance (CMR) is the most widely used approach for diagnosing myocardial fibrosis with late gadolinium enhancement (LGE) in cardiomyopathy associated with Duchenne muscular dystrophy. Given the limitations and safety of gadolinium use, we wanted to develop and evaluate multi-parametric pre-contrast CMR models for the diagnosis of LGE and investigate whether they could be utilised as surrogates for LGE in DMD patients. A total of 136 DMD patients were prospectively recruited and separated into LGE - and LGE + groups. In the first subset of patients (derivation cohort), regression models for the diagnosis of LGE were built by logistic regression using pre-contrast sequence parameters. In a validation cohort of other patients, the models' performances were evaluated. EF, native T1 and longitudinal strain alone, as well as their combinations form seven models. The model that included EF, native T1 and longitudinal strain had the best diagnostic value, but there was no significant difference in diagnostic accuracy among the other models except EF. In the validation cohort, the diagnosis outcomes of models were moderate consistent with the existence of LGE. The longitudinal strain outperformed the other models in terms of diagnostic value (sensitivity: 83.33%, specificity: 54.55%). Pre-contrast sequences have a moderate predictive value for LGE. Thus, pre-contrast parameters may be considered only in a specific subset of DMD patients who cannot cooperate for long-time examinations and have contradiction of contrast agent to help predict the presence of LGE. ChiCTR1800018340 DATE OF REGISTRATION: 20180107.


Zebrafish as a model to investigate CNS myelination.
Myelin plays a critical role in proper neuronal function by providing trophic and metabolic support to axons and facilitating energy-efficient saltatory conduction. Myelination is influenced by numerous molecules including growth factors, hormones, transmembrane receptors and extracellular molecules, which activate signaling cascades that drive cellular maturation. Key signaling molecules and downstream signaling cascades controlling myelination have been identified in cell culture systems. However, in vitro systems are not able to faithfully replicate the complex in vivo signaling environment that occurs during development or following injury. Currently, it remains time-consuming and expensive to investigate myelination in vivo in rodents, the most widely used model for studying mammalian myelination. As such, there is a need for alternative in vivo myelination models, particularly ones that can test molecular mechanisms without removing oligodendrocyte lineage cells from their native signaling environment or disrupting intercellular interactions with other cell types present during myelination. Here, we review the ever-increasing role of zebrafish in studies uncovering novel mechanisms controlling vertebrate myelination. These innovative studies range from observations of the behavior of single cells during in vivo myelination as well as mutagenesis- and pharmacology-based screens in whole animals. Additionally, we discuss recent efforts to develop novel models of demyelination and oligodendrocyte cell death in adult zebrafish for the study of cellular behavior in real time during repair and regeneration of damaged nervous systems.


Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma.
Inhibition of monocarboxylate transporter 1 has been proposed as a therapeutic approach to perturb lactate shuttling in tumor cells that lack monocarboxylate transporter 4. We examined the monocarboxylate transporter 1 inhibitor AZD3965, currently in phase I clinical studies, as a potential therapy for diffuse large B-cell lymphoma and Burkitt lymphoma. Whilst extensive monocarboxylate transporter 1 protein was found in 120 diffuse large B-cell lymphoma and 10 Burkitt lymphoma patients' tumors, monocarboxylate transporter 4 protein expression was undetectable in 73% of the diffuse large B-cell lymphoma samples and undetectable or negligible in each Burkitt lymphoma sample. AZD3965 treatment led to a rapid accumulation of intracellular lactate in a panel of lymphoma cell lines with low monocarboxylate transporter 4 protein expression and potently inhibited their proliferation. Metabolic changes induced by AZD3965 in lymphoma cells were consistent with a feedback inhibition of glycolysis. A profound cytostatic response was also observed in vivo: daily oral AZD3965 treatment for 24 days inhibited CA46 Burkitt lymphoma growth by 99%. Continuous exposure of CA46 cells to AZD3965 for 7 weeks in vitro resulted in a greater dependency upon oxidative phosphorylation. Combining AZD3965 with an inhibitor of mitochondrial complex I (central to oxidative phosphorylation) induced significant lymphoma cell death in vitro and reduced CA46 disease burden in vivo These data support clinical examination of AZD3965 in Burkitt lymphoma and diffuse large B-cell lymphoma patients with low tumor monocarboxylate transporter 4 expression and highlight the potential of combination strategies to optimally target the metabolic phenotype of tumors.


The role of the hok/sok locus in bacterial response to stressful growth conditions.
The hok/sok locus is renowned for its plasmid stabilization effect via post-segregational killing of plasmid-free daughter cells. However, the function(s) of the chromosome-encoded loci, which are more abundant in pathogenic strains of a broad range of enteric bacteria, are yet to be understood. Also, the frequent occurrence of this toxin/antitoxin addiction system in multi-drug resistance plasmids suggests additional roles. In this study, the effects of the hok/sok locus on the growth of bacteria in stressful growth-limiting conditions such as high temperature and antibiotic burden were investigated using hok/sok plasmids. The results showed that the hok/sok locus prolonged the lag phase of host cell cultures, thereby enabling the cells to adapt, respond to the stress and eventually thrive in these growth-limiting conditions by increasing the growth rate at exponential phase. The hok/sok locus also enhanced the survival and growth of cells in low cell density cultures irrespective of unfavourable growth conditions, and may complement existing or defective SOS mechanism. In addition to the plasmid stabilization function, these effects would enhance the ability of pathogenic bacteria to establish infections and propagate the antibiotic resistance elements carried on these plasmids, thereby contributing to the virulence of such bacteria.


Hypoxia and Local Inflammation in Pulmonary Artery Structure and Function.
Hypoxia is recognized as a contributor to pulmonary vascular diseases such as pulmonary hypertension. Hypoxia-induced inflammatory changes can enhance structural and functional changes in pulmonary artery (PA) in the context of PH. Accordingly, understanding how hypoxia and inflammation are linked in the context of pulmonary artery structure and function could be relevant towards development of novel therapies for PH. In this regard, factors such as thymic stromal lymphopoietin (TSLP), an inflammatory cytokine, and brain-derived neurotrophic factor (BDNF), a neurotrophin, have been found critical for nonvascular systems such as airway and asthma. While TSLP canonically affects the immune system, in nonvascular systems, noncanonical effects such as altered [Ca2+]i and cell proliferation have been noted: aspects also relevant to the PA, where there is currently little to no data. Similarly, better known in the nervous system, there is increasing evidence that BDNF is locally produced by structural cells of the airway and can contribute to asthma pathophysiology. In this chapter, we summarize the potential relevance of factors such as TSLP and BDNF to the PA and in the context of hypoxia influences towards development of PH. We focus on cell sources and targets such as PA endothelial cells (PAECs) and smooth muscle cells (PASMCs), and the effects of TSLP or BDNF on intracellular Ca2+ responses to vasoconstrictor agonist, cell proliferation, and potential signaling cascades involved.


The autophagic degradation of chloroplasts via rubisco-containing bodies is specifically linked to leaf carbon status but not nitrogen status in Arabidopsis.
Autophagy is an intracellular process facilitating the vacuolar degradation of cytoplasmic components and is important for nutrient recycling during starvation. We previously demonstrated that chloroplasts can be partially mobilized to the vacuole by autophagy via spherical bodies named Rubisco-containing bodies (RCBs). Although chloroplasts contain approximately 80% of total leaf nitrogen and represent a major carbon and nitrogen source for new growth, the relationship between leaf nutrient status and RCB production remains unclear. We examined the effects of nutrient factors on the appearance of RCBs in leaves of transgenic Arabidopsis (Arabidopsis thaliana) expressing stroma-targeted fluorescent proteins. In excised leaves, the appearance of RCBs was suppressed by the presence of metabolic sugars, which were added externally or were produced during photosynthesis in the light. The light-mediated suppression was relieved by the inhibition of photosynthesis. During a diurnal cycle, RCB production was suppressed in leaves excised at the end of the day with high starch content. Starchless mutants phosphoglucomutase and ADP-Glc pyrophosphorylase1 produced a large number of RCBs, while starch-excess mutants starch-excess1 and maltose-excess1 produced fewer RCBs. In nitrogen-limited plants, as leaf carbohydrates were accumulated, RCB production was suppressed. We propose that there exists a close relationship between the degradation of chloroplast proteins via RCBs and leaf carbon but not nitrogen status in autophagy. We also found that the appearance of non-RCB-type autophagic bodies was not suppressed in the light and somewhat responded to nitrogen in excised leaves, unlike RCBs. These results imply that the degradation of chloroplast proteins via RCBs is specifically controlled in autophagy.


Recovery from anesthesia. Hemodynamic consequences of emergence.
Attempts to attenuate the hemodynamic "emergence response" depend upon the availability and use of "real-time" physiological monitors. Such devices increase our diagnostic acuity and accuracy during this critical and labile period. Future investigation is needed to determine the effects of monitoring on morbidity and mortality, and is likely to lead to the development of guidelines and standards of care for the transport of emerging patients from the operating room to the PACU.


[Characterization of intra-population genetic polymorphism of the Colorado potato beetle using ISSR-markers and phenotypes].
The level of genetic diversity was estimated in a local population of Colorado potato beetle using ISSR-markers and specific pronotum patterns. In contrast to the unchanged level of diversity in ISSR, Shannon's diversity index calculated on the base of pronotum pattern variants was decreasing during summer testifying adaptivity of that sign. The results also show the difference in the level of genetic diversity of females comparing to males.


Endoscopic ultrasound (EUS)-guided angiotherapy of refractory gastrointestinal bleeding.
There are well-established methods for treating gastrointestinal (GI) bleeding, although some lesions prove refractory to conventional techniques. Little consideration has been directed toward the use of endoscopic ultrasound (EUS) in the management of refractory bleeding. To discuss patient selection, technique, and clinical outcomes for EUS-guided angiotherapy for severe refractory bleeding after conventional therapies. The EUS database was reviewed to identify all patients who underwent EUS-directed angiotherapy. Five patients, four with severe bleeding from hemosuccus pancreaticus, Dieulafoy lesion, duodenal ulcer, or gastrointestinal stromal tumor (GIST) and one with occult GI bleeding, had an average of three prior episodes (range 2-4) of severe bleeding and had received 18 (range 14-25) units of packed red blood cells (PRBC). All had failed in at least two conventional attempts to control the bleeding. Under EUS guidance, 99% alcohol was injected (4-7 mL) in two patients, one each with a pancreatic pseudoaneurysm and a duodenal Dieulafoy lesion. In three other patients, cyanoacrylate (3-5 mL) was injected into a duodenal ulcer, and in two patients with a GIST. No patient rebled and no complications were reported. EUS-guided angiotherapy appears safe and effective in managing selected patients with clinically severe or occult GI bleeding from lesions potentially refractory to standard endoscopic and/or angiographic techniques. Further studies are needed to confirm the safety and efficacy and to refine the selection criteria in an effort to improve patient care.


Digital photography in anatomical pathology.
Digital imaging has made major inroads into the routine practice of anatomical pathology and replaces photographic prints and Kodachromes for reporting and conference purposes. More advanced systems coupled to computers allow greater versatility and speed of turnaround as well as lower costs of incorporating macroscopic and microscopic pictures into pathology reports and publications. Digital images allow transmission to remote sites via the Internet for consultation, quality assurance and educational purposes, and can be stored on and disseminated by CD-ROM. Total slide digitisation is now a reality and will replace glass slides to a large extent. Three-dimensional images of gross specimens can be assembled and posted on websites for interactive educational programmes. There are also applications in research, allowing more objective and automated quantitation of a variety of morphological and immunohistological parameters. Early reports indicate that medical vision systems are a reality and can provide for automated computer-generated histopathological diagnosis and quality assurance.