A Versatile Isocyanate-Mediated Strategy for Appending Chemical Tags onto Drug-Like Small Molecules.
Target identification studies are a major hurdle in probe and drug discovery pipelines due to the need to chemically modify small molecules of interest, which can be time intensive and have low throughput. Here, we describe a versatile and scalable method for attaching chemical moieties to a small molecule, isocyanate-mediated chemical tagging (IMCT). By preparation of a template resin with an isocyanate capture group and a cleavable linker, nucleophilic groups on small molecules can be modified with an enforced one-to-one stoichiometry. We demonstrate a small molecule substrate scope that includes primary and secondary amines, thiols, phenols, benzyl alcohols, and primary alcohols. Cheminformatic analyses predict that IMCT is reactive with more than 25% of lead-like compounds in publicly available databases. To demonstrate that the method can produce biologically active molecules, we generated FKBP12 photoaffinity labeling (PAL) compounds with a wide range of affinities and showed that purified and crude cleavage products can bind to and label FKBP12. This method could be used to rapidly modify small molecules for many applications, including the synthesis of PAL probes, fluorescence polarization probes, pull-down probes, and degraders.


Quantum chaos and regularity in ultracold Fermi gases.
Quantum fluctuation of the energy is studied for an ultracold gas of interacting fermions trapped in a three-dimensional potential. Periodic-orbit theory is explored, and energy fluctuations are studied versus the particle number for generic regular and chaotic systems, as well as for a system defined by a harmonic confinement potential. Temperature effects on the energy fluctuations are investigated.


A Multicenter Study Evaluating the FREquency of Use and Efficacy of a Novel Closed-Loop Wearable Tibial Neuromodulation System for Overactive Bladder and Urgency Urinary Incontinence (FREEOAB).
To evaluate the effectiveness and safety of a novel wearable neuromodulation system incorporating embedded electromyographic evaluation, representing the first closed-loop wearable therapy for bladder control. This 12-week, multicenter, open-label, single-arm study of subjects with overactive bladder assessed response of bladder diary parameters and quality of life (QOL) metrics. Subjects used the transcutaneous tibial neuromodulation system, either once or three times weekly, with evaluations at weeks 1, 4, 8, and 12. Enrolled subjects (N = 96) were assessed for changes in urinary frequency, urgency, and urgency urinary incontinence episodes, and QOL changes using various questionnaires. In the intent-to-treat population (N = 96, mean age 60.8 ± 13.0years, 88.5% female), significant reductions in 3-day diary parameters were observed for daily voids, incontinence, and urgency episodes at 12weeks. QOL improvements exceeded the minimal clinically important difference for all QOL questionnaires. Long-term results remained robust at 12months. Device-related adverse events were mild and there were no device-related serious adverse events. Mean therapy compliance at 12weeks was 88.5%. High satisfaction rates were reported for the device overall. The Avation device demonstrates promising efficacy in treating adults with overactive bladder and urge urinary incontinence. At 12weeks, both diary parameters and QOL indicators showed significant improvement and remained robust at 12months. The device had a favorable safety profile with high compliance and patient satisfaction. This novel, closed-loop wearable tibial neuromodulation system represents a significant advancement in bladder control therapy, offering a noninvasive, patient-centered alternative with improved accessibility and ease of use.


Astrovirus-Associated Polioencephalomyelitis in an Alpaca.
An 8-year-old alpaca was admitted to the emergency service of the Clinic for Ruminants in Bern due to a reduced general condition and progressive neurological signs. Despite supportive treatment, its condition deteriorated and the animal had to be euthanized. Histopathological analysis revealed a severe non-suppurative polioencephalomyelitis with neuronal necrosis, most likely of viral origin. We detected abundant neuronal labelling with antibodies directed against two different epitopes of Bovine Astrovirus CH13/NeuroS1 (BoAstV-CH13/NeuroS1), which is a common viral agent associated with non-suppurative encephalitis in Swiss cattle. These findings were further verified by detection of viral RNA by use of in-situ hybridization and real-time RT-PCR. Next generation sequencing revealed that the detected virus genome had a pairwise identity of 98.9% to the genome of BoAstV-CH13/NeuroS1. To our knowledge, this is the first report of an astrovirus-associated polioencephalomyelitis in an alpaca. These results point to the possibility of an interspecies transmission of BoAstV-CH13/NeuroS1.


The activation efficiency of mechanophores can be modulated by adjacent polymer composition.
The activation efficiency of mechanophores in stress-responsive polymers is generally limited by the competing process of unspecific scission in other parts of the polymer chain. Here it is shown that the linker between the mechanophore and the polymer backbone determines the force required to activate the mechanophore. Using quantum chemical methods, it is demonstrated that the activation forces of three mechanophores (Dewar benzene, benzocyclobutene and gem-dichlorocyclopropane) can be adjusted over a range of almost 300% by modifying the chemical composition of the linker. The results are discussed in terms of changes in electron density, strain distribution and structural parameters during the rupture process. Using these findings it is straightforward to either significantly enhance or reduce the activation rate of mechanophores in stress-responsive materials, depending on the desired use case. The methodology is applied to switch a one-step "gating" of a mechanochemical transformation to a two-step process.


States with higher minimum wages have lower STI rates among women: Results of an ecological study of 66 US metropolitan areas, 2003-2015.
Prior research has found that places and people that are more economically disadvantaged have higher rates and risks, respectively, of sexually transmitted infections (STIs). Economic disadvantages at the level of places and people, however, are themselves influenced by economic policies. To enhance the policy relevance of STI research, we explore, for the first time, the relationship between state-level minimum wage policies and STI rates among women in a cohort of 66 large metropolitan statistical areas (MSAs) in the US spanning 2003-2015. Our annual state-level minimum wage measure was adjusted for inflation and cost of living. STI outcomes (rates of primary and secondary syphilis, gonorrhea and chlamydia per 100,000 women) were obtained from the CDC. We used multivariable hierarchical linear models to test the hypothesis that higher minimum wages would be associated with lower STI rates. We preliminarily explored possible socioeconomic mediators of the minimum wage/STI relationship (e.g., MSA-level rates of poverty, employment, and incarceration). We found that a $1 increase in the price-adjusted minimum wage over time was associated with a 19.7% decrease in syphilis rates among women and with an 8.5% drop in gonorrhea rates among women. The association between minimum wage and chlamydia rates did not meet our cutpoint for substantive significance. Preliminary mediation analyses suggest that MSA-level employment among women may mediate the relationship between minimum wage and gonorrhea. Consistent with an emerging body of research on minimum wage and health, our findings suggest that increasing the minimum wage may have a protective effect on STI rates among women. If other studies support this finding, public health strategies to reduce STIs among women should include advocating for a higher minimum wage.


The story of George Huntington and his disease.
George Huntington described some families with choreiform movements in 1872 in the United States of America and since then many such families have been described in other parts of the world and works on the genetics of the disease have brought new vistas in the understanding of the disease. In 1958, Americo Negrette, a young Venezuelan physician observed similar subjects in the vicinity of Lake Maracaibo which was presented by his co-worker, Ramon Avilla Giron at New York in 1972 when United States of America had been commemorating the centenary year of Huntington's disease. Nancy Wexler, a psychoanalyst, whose mother had been suffering from the disease attended the meeting and organized a research team to Venezuela and they systematically studied more than 18,000 individuals in order to work out a common pedigree. They identified the genetic locus of the disease in the short arm of chromosome 4 and observed that it was a trinucleotide repeat disorder.


Immune cell infiltration in corneas of mice with recurrent herpes simplex virus disease.
Reactivation of latent herpes simplex virus type 1 (HSV-1) infection was induced by UV irradiation of the corneas of latently infected mice. On days 1-4 after stimulation, infectious virus was sought in nervous and ocular tissue. On days 4, 7 and 10, eyes with either recurrent epithelial or stromal disease and appropriate controls were stained to identify immune cells and HSV-1 antigens. The maximum incidence of infectious virus was on day 2 when 5/10 ophthalmic parts of the trigeminal ganglion yielded HSV. Thus in this mouse model, as in humans, reactivation of virus in the trigeminal ganglion is the likely source of virus producing recurrent disease and shedding in the tear film. On day 4, when virus antigens were still present, granulocytes were the predominant infiltrating cell in corneas with either type of disease. Small numbers of T cells, dendritic cells and cells expressing MHC class II were also present. In stromal disease, the granulocyte infiltrate persisted and T cells remained sparse. In contrast, in epithelial disease, granulocyte numbers rapidly declined and both CD4+ and CD8+ T cells (present at a ratio of 1:1) increased significantly. The secondary immune response to virus antigen is more rapid and vigorous than that during primary corneal infection. Granulocytes may play a role in the initial clearance of virus, however, the other types of cells present early on provide the potential for a local secondary immune response. The high proportion of CD8+ cells in epithelial disease compared with stromal disease suggests that they may be acting as suppressors.


Plasmonic Nanomaterial-Based Optical Biosensing Platforms for Virus Detection.
Plasmonic nanomaterials (P-NM) are receiving attention due to their excellent properties, which include surface-enhanced Raman scattering (SERS), localized surface plasmon resonance (LSPR) effects, plasmonic resonance energy transfer (PRET), and magneto optical (MO) effects. To obtain such plasmonic properties, many nanomaterials have been developed, including metal nanoparticles (MNP), bimetallic nanoparticles (bMNP), MNP-decorated carbon nanotubes, (MNP-CNT), and MNP-modified graphene (MNP-GRP). These P-NMs may eventually be applied to optical biosensing systems due to their unique properties. Here, probe biomolecules, such as antibodies (Ab), probe DNA, and probe aptamers, were modified on the surface of plasmonic materials by chemical conjugation and thiol chemistry. The optical property change in the plasmonic nanomaterials was monitored based on the interaction between the probe biomolecules and target virus. After bioconjugation, several optical properties, including fluorescence, plasmonic absorbance, and diffraction angle, were changed to detect the target biomolecules. This review describes several P-NMs as potential candidates of optical sensing platforms and introduces various applications in the optical biosensing field.


Leaf anatomical and photosynthetic acclimation to cool temperature and high light in two winter versus two summer annuals.
Acclimation of foliar features to cool temperature and high light was characterized in winter (Spinacia oleracea L. cv. Giant Nobel; Arabidopsis thaliana (L.) Heynhold Col-0 and ecotypes from Sweden and Italy) versus summer (Helianthus annuus L. cv. Soraya; Cucurbita pepo L. cv. Italian Zucchini Romanesco) annuals. Significant relationships existed among leaf dry mass per area, photosynthesis, leaf thickness and palisade mesophyll thickness. While the acclimatory response of the summer annuals to cool temperature and/or high light levels was limited, the winter annuals increased the number of palisade cell layers, ranging from two layers under moderate light and warm temperature to between four and five layers under cool temperature and high light. A significant relationship was also found between palisade tissue thickness and either cross-sectional area or number of phloem cells (each normalized by vein density) in minor veins among all four species and growth regimes. The two winter annuals, but not the summer annuals, thus exhibited acclimatory adjustments of minor vein phloem to cool temperature and/or high light, with more numerous and larger phloem cells and a higher maximal photosynthesis rate. The upregulation of photosynthesis in winter annuals in response to low growth temperature may thus depend on not only (1) a greater volume of photosynthesizing palisade tissue but also (2) leaf veins containing additional phloem cells and presumably capable of exporting a greater volume of sugars from the leaves to the rest of the plant.


Intravenous Honokiol in Drug-Resistant Cancer: Two Case Reports.
Context: Long-term patient survival in cancer is affected by drug resistance. Honokiol (HNK) is a small-molecule polyphenol isolated from the bark and seed cones of Magnolia officinalis. HNK has been shown to enhance the effects of chemotherapy and inhibit drug resistance in preclinical models. HNK was well tolerated in multiple animal models when administered orally, intravenously (IV), and via intraperitoneal route. However, there are limited human data on the use of HNK in general, and specifically via IV (HNK-IV) in cancer. Objective: We aim to assess the efficacy, safety, and tolerability of HNK-IV in patients with drug-resistant tumors. Methods: This is a case study of 2 cancer patients who utilized HNK-IV as part of their cancer treatment regimen. The initial infusion of HNK was 10 mg/kg body weight, and subsequent treatments were increased up to 50 mg/kg according to individual tolerance, over 2 weeks. Results: Positive clinical response was achieved in both patients, including improved symptoms and quality of life. No serious adverse side effects occurred, and there were no adverse effects on laboratory parameters (complete blood count, kidney, and liver function). Transient sedation and minor nausea were noted and resolved postinfusion. Conclusions: This is the first report of HNK-IV in human patients. Given the positive clinical results, safety, and tolerability, the use of HNK-IV warrants further investigation regarding optimum formulation, and its use as adjunctive therapy in cancer patients.


Assessment of left ventricular hypertrophy in patients with essential hypertension.
By virtue of its potency as a cardiovascular risk indicator, the presence of left ventricular hypertrophy (LVH) in a patient with hypertension deserves serious attention and make its diagnosis a clinical priority. In view of its prognostic impact, an argument could be made for routine assessment of this intermediate endpoint in each patient with essential hypertension. Two diagnostic approaches are available for screening evaluation of hypertensive patients; either a limited echocardiographic examination or an ECG-based LVH assessment. Recently developed new or combined criteria have significantly improved the diagnostic performance of ECG criteria, and evolving data show that accurate estimation of LVH can be performed by ECG screening in a majority of patients. At present, ECG evaluation based either on sex-specific orthogonal-lead time-voltage criteria or on the combined standard 12-lead criteria of Sokolow-Lyon (sum of S in V1 and R in V5 or V6) or Cornell Product (product of sum of R in aVL and S in V3 + 6 mm in females and QRS duration) demonstrates the best overall diagnostic accuracy. With orthogonal criteria, the sensitivity is 81% in women and 71% in men at a matched 98% specificity. The corresponding overall sensitivity of the combined Cornell Product or Sokolow-Lyon criteria is reported to be 68% at a specificity of 96.6%. What speaks in favour of the echocardiographic approach is its superior sensitivity and the possibility of gaining additional potential risk information associated with the geometric pattern of the LVH. However, its general availability makes electrocardiography a cost-effective diagnostic alternative with which to follow the progression or regression of LVH in hypertensive patients.


Linear eccrine poroma.
A 44-year-old woman had multiple papular lesions of 20 years' duration. The lesions were limited to the right lower extremity and were arranged in a linear fashion. They had the histologic appearance of eccrine poroma; however, thin intertwining strands of tumor cells extended down into the dermis in a pattern similar to that of premalignant fibroepithelioma. Also, bud-like proliferations of tumor cells were attached to the epidermis, analogous to those superficial basal cell epithelioma. A dilated cystic duct resembling that found in syringoma was present in the upper part of the dermis. To my knowledge, such a linear distribution of multiple eccrine poromas has not been reported in the dermatologic literature.


Cardiac troponin I, cardiac troponin T, and creatine kinase MB in dialysis patients without ischemic heart disease: evidence of cardiac troponin T expression in skeletal muscle.
Serum cardiac troponin T (cTnT) concentrations are frequently increased in chronic dialysis patients as measured by the first-generation ELISA immunoassay, as is creatine kinase (CK) MB mass in the absence of acute ischemic heart disease. We designed this study to compare four serum markers of myocardial injury [CK-MB mass, first-generation ELISA cTnT, second-generation Enzymun cTnT, and cardiac troponin I (cTnI)] in dialysis patients without acute ischemic heart disease. We also evaluated skeletal muscle from dialysis patients as a potential source of serum cTnT. No patients in the clinical evaluation group (n = 24) studied by history and by physical examination, electrocardiography, and two-dimensional echocardiography had evidence of ischemic heart disease. Biochemical markers were measured in serial predialysis blood samples with specific monoclonal antibody-based immunoassays. For several patients at least one sample measured above the upper reference limit: CK-MB, 7 of 24 (30%); ELISA cTnT, 17 of 24 (71%); Enzymun cTnT, 3 of 18 (17%); and cTnI, 1 of 24 (4%). In a separate group of dialysis patients (n = 5), expression of cTnT, but not cTnI, was demonstrated by Western blot analysis in 4 of 5 skeletal muscle biopsies. Chronic dialysis patients without acute ischemic heart disease frequently had increased serum CK-MB and cTnT. The specificity of the second-generation cTnT (Enzymun) assay was improved over that of the first-generation (ELISA) assay; cTnI was the most specific of the currently available biochemical markers. cTnT, but not cTnI, was expressed in the skeletal muscle of dialysis patients.


Nanocomposite-coated porous templates for engineered bone scaffolds: a parametric study of layer-by-layer assembly conditions.
Using the layer-by-layer (LbL) assembly technique to deposit mechanically reinforcing coatings onto porous templates is a route for fabricating engineered bone scaffold materials with a combination of high porosity, strength, and stiffness. LbL assembly involves the sequential deposition of nano- to micro-scale multilayer coatings from aqueous solutions. Here, a design of experiments (DOE) approach was used to evaluate LbL assembly of polyethyleneimine (PEI), polyacrylic acid (PAA), and nanoclay coatings onto open-cell polyurethane foam templates. The thickness of the coatings, and the porosity, elastic modulus and collapse stress of coated foam templates were most strongly affected by the pH of PAA solutions, salt concentration, and interactions between these factors. The mechanical properties of coated foams correlated with the thickness of the coatings, but were also ascribed to changes in the coating properties due to the different assembly conditions. A DOE optimization aimed to balance the trade-off between higher mechanical properties but lower porosity of foam templates with increasing coating thickness. Micromechanical modeling predicted that deposition of 116 QLs would achieve mechanical properties of cancellous bone (>0.05 GPa stiffness and >2 MPa strength) at a suitable porosity of >70%. When capped with a final layer of PAA and cross-linked via thermal treatment, the PEI/PAA/PEI/nanoclay coatings exhibited good indirect cytotoxicity with mesenchymal stem cells. The ability of LbL assembly to deposit a wide range of functional constituents within multilayer-structured coatings makes the general strategy of templated LbL assembly a powerful route for fabricating engineered tissue scaffolds that can be applied onto various porous template materials to achieve a wide range of properties, pore structures, and multifunctionality.


Drinking and driving pancreatitis: links between endoplasmic reticulum stress and autophagy.
Alcohol abuse is the leading etiologic factor of pancreatitis, although many heavy drinkers do not develop pancreatic damage. Alcohol promotes pancreatitis through a combination of remote (e.g., increased gut permeability to bacterial products such as lipopolysaccharide) and more proximal effects (e.g., altered pancreatic cholinergic inputs), including oxidative damage at the level of the pancreatic acinar cell. Recent evidence indicates that alcohol exposure to rodents disturbs proteostasis in the exocrine pancreas, an effect counterbalanced by homeostatic processes that include both the unfolded protein response (UPR) and autophagy. A corollary to this notion is that pancreatitis results when adaptive responses are insufficiently robust to alleviate the cellular stress caused by alcohol.


Identification of mouse retinal genes differentially regulated by dim and bright cyclic light rearing.
Bright cyclic light rearing protects BALB/c mice from light-induced photoreceptor apoptosis compared to dim cyclic light rearing. We used a microarray approach to search for putative neuroprotection genes that were up- or down-regulated under these environmental conditions. Retinal protection by bright cyclic rearing was determined by quantitative histology and DNA fragmentation analysis. Total RNA was isolated from 5-week-old mice raised in bright (400 lux) or dim (5 lux) cyclic light and prepared for analysis on microarrays produced using a 70-mer oligonucleotide library that represented 16,463 mouse genes. Genes of interest were identified using statistically robust bioinformatics analysis methods that were developed in-house. Changes in some genes were confirmed with quantitative real time PCR. We found that 952 genes were up- or down-regulated by bright cyclic light rearing compared to dim cyclic light rearing. One hundred and eighty-four of them, having >/=2-fold differences, were grouped into 13 categories, and selected for further consideration. Eleven up-regulated and two down-regulated genes were confirmed by semi-quantitative PCR. Five neuroprotection-associated genes were up-regulated by bright cyclic light rearing as confirmed by real-time PCR. The human orthologue chromosomal location of 22 differentially expressed genes map to known retinal degeneration loci. Using PathwayAssist software, we modeled the pathway networks of up- and down-regulated genes that are functionally related to the retina. We identified retinal genes that are differentially regulated by environmental light history. Those that directly affect cell processes such as survival, apoptosis, and transcription are likely play a pivotal role in the regulation of retinal neuroprotection against light-induced photoreceptor apoptosis.


Essential role for a novel population of binucleated mammary epithelial cells in lactation.
The mammary gland represents a unique tissue to study organogenesis as it predominantly develops in the post-natal animal and undergoes dramatic morphogenetic changes during puberty and the reproductive cycle. The physiological function of the mammary gland is to produce milk to sustain the newborn. Here we view the lactating gland through three-dimensional confocal imaging of intact tissue. We observed that the majority of secretory alveolar cells are binucleated. These cells first arise in very late pregnancy due to failure of cytokinesis and are larger than mononucleated cells. Augmented expression of Aurora kinase-A and Polo-like kinase-1 at the lactogenic switch likely mediates the formation of binucleated cells. Our findings demonstrate an important physiological role for polyploid mammary epithelial cells in lactation, and based on their presence in five different species, suggest that binucleated cells evolved to maximize milk production and promote the survival of offspring across all mammalian species.


Treatment efficacy and immune stimulation by AdCD40L gene therapy of spontaneous canine malignant melanoma.
Malignant melanoma is a serious disease in both humans and dogs, and the high metastatic potential results in poor prognosis for many patients. Its similarities with human melanoma make spontaneous canine melanoma an excellent model for comparative studies of novel therapies and tumor biology. We report a pilot study of local adenovector CD40L (AdCD40L) immunogene treatment in 19 cases of canine melanoma (14 oral, 4 cutaneous, and 1 conjunctival). Three patients were World Health Organization stage I, 2 were stage II, 10 stage III, and 4 stage IV. One to 6 intratumoral injections of AdCD40L were given every 7 days, followed by cytoreductive surgery in 9 cases and only immunotherapy in 10 cases. Tumor tissue was infiltrated with T and B lymphocytes after treatment, suggesting immune stimulation. The best overall response included 5 complete responses, 8 partial responses, and 4 stable and 2 progressive disease statuses according to the World Health Organization response criteria. Median survival was 160 days (range, 20-1141 d), with 3 dogs still alive at submission. Our results suggest that local AdCD40L therapy is safe and could have beneficial effects in dogs, supporting further treatment development. Clinical translation to human patients is in progress.


Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma.
A pilot study of 43 patients with potentially resectable esophageal carcinoma treated with an intensive regimen of preoperative chemoradiation with cisplatin, fluorouracil, and vinblastine before surgery showed a median survival of 29 months in comparison with the 12-month median survival of 100 historical controls treated with surgery alone at the same institution. We designed a randomized trial to compare survival for patients treated with this preoperative chemoradiation regimen versus surgery alone. One hundred patients with esophageal carcinoma were randomized to receive either surgery alone (arm I) or preoperative chemoradiation (arm II) with cisplatin 20 mg/m2/d on days 1 through 5 and 17 through 21, fluorouracil 300 mg/m2/d on days 1 through 21, and vinblastine 1 mg/m2/d on days 1 through 4 and 17 through 20. Radiotherapy consisted of 1.5-Gy fractions twice daily, Monday through Friday over 21 days, to a total dose of 45 Gy. Transhiatal esophagectomy with a cervical esophagogastric anastomosis was performed on approximately day 42. At median follow-up of 8.2 years, there is no significant difference in survival between the treatment arms. Median survival is 17.6 months in arm I and 16.9 months in arm II. Survival at 3 years was 16% in arm I and 30% in arm II (P = .15). This study was statistically powered to detect a relatively large increase in median survival from 1 year to 2.2 years, with at least 80% power. This randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.


The immune epitope database (IEDB) 3.0.
The IEDB, www.iedb.org, contains information on immune epitopes--the molecular targets of adaptive immune responses--curated from the published literature and submitted by National Institutes of Health funded epitope discovery efforts. From 2004 to 2012 the IEDB curation of journal articles published since 1960 has caught up to the present day, with >95% of relevant published literature manually curated amounting to more than 15,000 journal articles and more than 704,000 experiments to date. The revised curation target since 2012 has been to make recent research findings quickly available in the IEDB and thereby ensure that it continues to be an up-to-date resource. Having gathered a comprehensive dataset in the IEDB, a complete redesign of the query and reporting interface has been performed in the IEDB 3.0 release to improve how end users can access this information in an intuitive and biologically accurate manner. We here present this most recent release of the IEDB and describe the user testing procedures as well as the use of external ontologies that have enabled it.


Internal and external sources of variability in perceptual decision-making.
It is important to identify sources of variability in processing to understand decision-making in perception and cognition. There is a distinction between internal and external variability in processing, and double-pass experiments have been used to estimate their relative contributions. In these and our experiments, exact perceptual stimuli are repeated later in testing, and agreement on the 2 trials is examined to see if it is greater than chance. In recent research in modeling decision processes, some models implement only (internal) variability in the decision process whereas others explicitly represent multiple sources of variability. We describe 5 perceptual double-pass experiments that show greater than chance agreement, which is inconsistent with models that assume internal variability alone. Estimates of total trial-to-trial variability in the evidence accumulation (drift) rate (the decision-relevant stimulus information) were estimated from fits of the standard diffusion decision-making model to the data. The double-pass procedure provided estimates of how much of this total variability was systematic and dependent on the stimulus. These results provide the first behavioral evidence independent of model fits for trial-to-trial variability in drift rate in tasks used in examining perceptual decision-making. (PsycINFO Database Record


Mitochondrial genomics in Orthoptera using MOSAS.
We present complete mitochondrial genomes (mitogenomes) for three orthopterans (Xyleus modestus, Physemacris variolosa, and Ellipes minuta) and describe MOSAS (manipulation, organization, storage, and analysis of sequences), software we developed to facilitate annotation and analysis. We analyze the base composition, start and stop codons, non-coding regions, and gene order among these and 18 other orthopteran mitogenomes from GenBank and reconstruct a phylogeny of Orthoptera. We propose a tetranucleotide start codon for cox1, and hypothesize that the tRNA(Asp)-tRNA(Lys) rearrangement is a synapomorphy for Acridomorpha, but not Caelifera. We further describe MOSAS, user-friendly software we used for this analysis. MOSAS streamlines sequence data storage, organization, annotation, and alignment, and provides convenient search tools for dataset construction and a robust annotation engine particularly suited to annotating mitogenomes (available at http://mosas.byu.edu).


4 × 160-Gbit/s multi-channel regeneration in a single fiber.
Simultaneous regeneration of four high-speed (160 Gbit/s) wavelength-division multiplexed (WDM) and polarization-division multiplexed (PDM) signals in a single highly nonlinear fiber (HNLF) is demonstrated. The regeneration operation is based on four-wave mixing in HNLF, where the degraded data signals are applied as the pump. As a result, the noise on both '0' and '1' levels can be suppressed simultaneously in our scheme. The stimulated Brillouin scattering (SBS) from the continuous wave (CW) is suppressed by cross-phase modulation (XPM) from the data pump, relieving the requirement of external phase modulation of the CW light. Mitigation of the inter-channel nonlinearities is achieved mainly through an inter-channel 0.5 bit slot time delay. Bidirectional propagation is also applied to relieve the inter-channel four-wave mixing. The multi-channel regeneration performance is validated by bit-error rate (BER) measurements. The receiver powers at the BER of 10(-9) are improved by 1.9 dB, 1.8 dB, 1.6 dB and 1.5 dB for the four data channels, respectively.


Behavioral effects in the rat of dihydrexidine, a high-potency, full-efficacy D1 dopamine receptor agonist.
Dihydrexidine (trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phena nthridine) was reported recently to be the first full efficacy, potent D1 receptor agonist, but one also having some potency for D2 receptors. This study reports the effects of dihydrexidine on behavior of the rat. In study 1, the dose-response relationships of dihydrexidine (0.3 to 30 mg/kg) to various behaviors were assessed using direct observations. The frequency of three behaviors (grooming, sniffing, and locomotion) was significantly increased by this drug. The dose-response curve for drug-induced grooming approximated an inverted U shape. Dihydrexidine increased locomotion at two of the higher doses (3 and 30 mg/kg), and increased sniffing at doses greater than or equal to 1.0 mg/kg. Other behavioral topographies, such as licking, gnawing, and rearing, were not systematically affected by drug administration. Also, there was no indication of convulsion in any dihydrexidine-treated rat. In study 2, rats were pretreated with either the selective D1 antagonist SCH23390 or the selective D2 antagonist remoxipride prior to receiving dihydrexidine. SCH23390 antagonized the effects of dihydrexidine on grooming, locomotion, and sniffing. Conversely, remoxipride blocked dihydrexidine-induced locomotion, but had no effect on dihydrexidine-induced grooming or sniffing. Numerous behaviors are believed to be mediated by the interactions of D1 and D2 receptors. These data indicate that dihydrexidine can be an important tool for characterizing both the behavioral actions of D1 receptors, and the nature of D1/D2 interactions in mammalian brain. In addition, its high potency and full efficacy at D1 receptors, coupled with its significant D2 properties, may provide specific utility in certain clinical situations.


An observational study on the relationship between serum uric acid and hypertension in a Northern Chinese population aged 45 to 59 years.
Little is known about the relationship serum uric acid (SUA) and hypertension in Chinese population. Therefore, the aim of this study was to determine the association between SUA and hypertension in a northern Chinese population. The participants were a group of 1730 Chinese adults aged 45 to 59 years in Shandong Province, who were recruited from the Linyi Nutrition and Health Survey (2015-2016). Hypertension was defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg. Hyperuricemia was defined as SUA >420 μmol/L (7.0 mg/dL) for men and >360 μmol/L (6.0 mg/dL) for women. All anthropometric measurements and biochemical data were collected following standard protocols. Multivariate logistic regression analysis was used to examine the association between SUA and hypertension with adjustment of confounding variables. Body mass index, waist circumference, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, fasting blood glucose, triglycerides, alanine aminotransferase, aspartate aminotransferase, SUA, and the prevalence of hypertension and hyperuricemia were significantly higher in males than in females (P < .001). The females had significantly higher levels of total cholesterol and high-density lipoprotein cholesterol. Besides, after adjustment for confounding variables, hyperuricemia was associated with an increased risk of hypertension in both male and female patients, with odds ratios of 2.152 (95% confidence interval 1.324-3.498) and 2.133(95% confidence interval 1.409-3.229), respectively.Hyperuricemia was significantly associated with the risk of hypertension. Further longitudinal studies and trails are needed to confirm our findings.


Co-occurrence patterns of bacteria within microbiome of Moscow subway.
Microbial ecosystems of the built environments have become key mediators of health as people worldwide tend to spend large amount of time indoors. Underexposure to microbes at an early age is linked to increased risks of allergic and autoimmune diseases. Transportation systems are of particular interest, as they are globally the largest space for interactions between city-dwellers. Here we performed the first pilot study of the Moscow subway microbiome by analyzing swabs collected from 5 types of surfaces at 4 stations using high-throughput 16S rRNA gene sequencing. The study was conducted as a part of The Metagenomics and Metadesign of the Subways and Urban Biomes (MetaSUB) project. The most abundant microbial taxa comprising the subway microbiome originated from soil and human skin. Microbiome diversity was positively correlated with passenger traffic. No substantial evidence of major human pathogens presence was found. Co-occurrence analysis revealed clusters of microbial genera including combinations of microbes likely originating from different niches. The clusters as well as the most abundant microbes were similar to ones obtained for the published data on New-York City subway microbiome. Our results suggest that people are the main source and driving force of diversity in subway-associated microbiome. The data form a basis for a wider survey of Moscow subway microbiome to explore its longitudinal dynamics by analyzing an extended set of sample types and stations. Complementation of methods with viability testing, "shotgun" metagenomics, sequencing of bacterial isolates and culturomics will provide insights for public health, biosafety, microbial ecology and urban design.


Ethyl methane sulfonate induced mutations in M2 generation and physiological variations in M1 generation of peppers (Capsicum annuum L.).
This study was conducted to enhance genetic variability in peppers (Capsicum annuum, cv B12) using ethyl methanesulphonate (EMS). Exposure to an EMS concentration of 0.6%, v/v for 12 h was used to mutagenize 2000 seeds for the first generation (M1). It was observed that the growth behaviors including plant height, flowering date, and number of seeds per first fruit were different in the M1 generation than in wild type (WT) plants. In addition one phenotypic mutation (leaf shape and plant architecture) was observed during the M1 generation. During the seedling stage in the M2 generation, the observed changes were in the form of slow growth or chlorophyll defect (e.g., albino, pale green, and yellow seedlings). At maturity, there were three kinds of phenotypic mutations observed in three different families of the mutant population. The first observed change was a plant with yellow leaf color, and the leaves of this mutant plant contained 62.19% less chlorophyll a and 64.06% less chlorophyll b as compared to the wild-type. The second mutation resulted in one dwarf plant with a very short stature (6 cm), compact internodes and the leaves and stem were rough and thick. The third type of mutation occurred in four plants and resulted in the leaves of these plants being very thick and longer than those of WT plants. Furthermore, anatomical observations of the leaf blade section of this mutant plant type contained more xylem and collenchyma tissue in the leaf midrib of the mutant plant than WT. In addition, its leaf blade contained thicker palisade and spongy tissue than the WT.


Interspecific common bean population derived from Phaseolus acutifolius using a bridging genotype demonstrate useful adaptation to heat tolerance.
Common bean (Phaseolus vulgaris L.) is an important legume crop worldwide and is a major nutrient source in the tropics. Common bean reproductive development is strongly affected by heat stress, particularly overnight temperatures above 20°C. The desert Tepary bean (Phaseolus acutifolius A. Gray) offers a promising source of adaptative genes due to its natural acclimation to arid conditions. Hybridization between both species is challenging, requiring in vitro embryo rescue and multiple backcrossing cycles to restore fertility. This labor-intensive process constrains developing mapping populations necessary for studying heat tolerance. Here we show the development of an interspecific mapping population using a novel technique based on a bridging genotype derived from P. vulgaris, P. Acutifolius and P. parvifolius named VAP1 and is compatible with both common and tepary bean. The population was based on two wild P. acutifolius accessions, repeatedly crossed with Mesoamerican elite common bush bean breeding lines. The population was genotyped through genotyping-by-sequencing and evaluated for heat tolerance by genome-wide association studies. We found that the population harbored 59.8% introgressions from wild tepary, but also genetic regions from Phaseolus parvifolius, a relative represented in some early bridging crosses. We found 27 significative quantitative trait loci, nine located inside tepary introgressed segments exhibiting allelic effects that reduced seed weight, and increased the number of empty pods, seeds per pod, stem production and yield under high temperature conditions. Our results demonstrate that the bridging genotype VAP1 can intercross common bean with tepary bean and positively influence the physiology of derived interspecific lines, which displayed useful variance for heat tolerance.


Role of PP2A in intracellular signal transduction pathways.
Intracellular signal transduction pathways play a crucial role in a variety of cellular processes, such as differentiation, proliferation, or apoptosis, and the reversible phosphorylation of their components is a major regulatory mechanism to control their activities. While much has been learned about the contribution of kinases, the involvement of phosphatases in these events is less clear and has only recently received more investigative attention. The availability of various natural product inhibitors of phosphatases has helped enormously to gain insight into the role that these enzymes exert in various signal transduction processes. This review will focus on serine/threonine protein phosphatase type 2A (PP2A) and will present findings pertaining to its involvement in cellular signal transduction pathways. Since the majority of these studies were done with the use of phosphatase inhibitory compounds, some pros and cons of their application will be presented.


Novel Potential Therapeutic Targets of PTPN Families for Lung Cancer.
Despite the treatment of lung adenocarcinoma (LUAD) having partially improved in recent years, LUAD patients still have poor prognosis rates. Therefore, it is especially important to explore effective biomarkers and exploit novel therapeutic developments. High-throughput technologies are widely used as systematic approaches to explore differences in expressions of thousands of genes for both biological and genomic systems. Recently, using big data analyses in biomedicine research by integrating several high-throughput databases and tools, including The Cancer Genome Atlas (TCGA), cBioportal, Oncomine, and Kaplan-Meier plotter, is an important strategy to identify novel biomarkers for cancer therapy. Here, we used two different comprehensive bioinformatics analysis and revealed protein tyrosine phosphatase non-receptor type (PTPN) family genes, especially PTPN1 and PTPN22, were downregulated in lung cancer tissue in comparison with normal samples. The survival curves indicated that LUAD patients with high transcription levels of PTPN5 were significantly associated with a good prognosis. Meanwhile, Gene Ontology (GO) and MetaCore analyses indicated that co-expression of the PTPN1, PTPN5, and PTPN21 genes was significantly enriched in cancer development-related pathways, including GTPase activity, regulation of small GTPase-mediated signal transduction, response to mechanical stimuli, vasculogenesis, organ morphogenesis, regulation of stress fiber assembly, mitogen-activated protein kinase (MAPK) cascade, cell migration, and angiogenesis. Collectively, this study revealed that PTPN family members are both significant prognostic biomarkers for lung cancer progression and promising clinical therapeutic targets, which provide new targets for treating LUAD patients.


Normal hematopoietic stem cells within the AML bone marrow have a distinct and higher ALDH activity level than co-existing leukemic stem cells.
Persistence of leukemic stem cells (LSC) after chemotherapy is thought to be responsible for relapse and prevents the curative treatment of acute myeloid leukemia (AML) patients. LSC and normal hematopoietic stem cells (HSC) share many characteristics and co-exist in the bone marrow of AML patients. For the development of successful LSC-targeted therapy, enabling eradication of LSC while sparing HSC, the identification of differences between LSC and HSC residing within the AML bone marrow is crucial. For identification of these LSC targets, as well as for AML LSC characterization, discrimination between LSC and HSC within the AML bone marrow is imperative. Here we show that normal CD34+CD38- HSC present in AML bone marrow, identified by their lack of aberrant immunophenotypic and molecular marker expression and low scatter properties, are a distinct sub-population of cells with high ALDH activity (ALDH(bright)). The ALDH(bright) compartment contains, besides normal HSC, more differentiated, normal CD34+CD38+ progenitors. Furthermore, we show that in CD34-negative AML, containing solely normal CD34+ cells, LSC are CD34- and ALDH(low). In CD34-positive AML, LSC are also ALDH(low) but can be either CD34+ or CD34-. In conclusion, although malignant AML blasts have varying ALDH activity, a common feature of all AML cases is that LSC have lower ALDH activity than the CD34+CD38- HSC that co-exist with these LSC in the AML bone marrow. Our findings form the basis for combined functionally and immunophenotypically based identification and purification of LSC and HSC within the AML bone marrow, aiming at development of highly specific anti-LSC therapy.


DNA Methylation Research in Autologous Hematopoietic Stem Cell Transplant Population.
Despite increased sophistication in DNA methylation (DNAm) measurement and methods, conducting studies in specific populations such as the hematopoietic stem cell transplant (HCT) population, presents unique challenges and study design considerations. In this article, we explain the motivation for investigating DNAm in the HCT population, highlighting important study design features and key findings in a longitudinal prospective pilot study of DNAm in 32 patients undergoing autologous HCT in Central Virginia, USA. We also discuss limitations and challenges to generating robust results. We observed that HCT does not prevent high-quality DNA from being extracted from whole blood for DNAm research and that longitudinal prospective studies that span pre- and 2-months post-HCT are feasible. Critically, we did not observe significant impacts of cancer diagnosis, time since transplant, age, or chromosomal sex on overall DNAm data dimensionality. These observations demonstrate that while extreme care is required to ensure generalizable, accurate, and interpretable results, researchers should not avoid HCT-DNAm research simply for fear that the transplant procedure or presence of a cancer diagnosis will prevent meaningful conclusions from being drawn. DNAm is an attractive biomarker that is understudied in patients undergoing HCT and needs to expand to improve precise prediction of HCT outcomes.


The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status.
We recently characterized gene expression patterns in gastrointestinal stromal tumors (GISTs) using cDNA microarrays, and found that the gene FLJ10261 (DOG1, discovered on GIST-1), encoding a hypothetical protein, was specifically expressed in GISTs. The immunoreactivity of a rabbit antiserum to synthetic DOG1 peptides was assessed on two soft tissue tumor microarrays. The tissue microarrays included 587 soft tissue tumors, with 149 GISTs, including 127 GIST cases for which the KIT and PDGFRA mutation status was known. Immunoreactivity for DOG1 was found in 136 of 139 (97.8%) of scorable GISTs. All seven GIST cases with a PDGFRA mutation were DOG1-positive, while most of these failed to react for KIT. The immunohistochemical findings were confirmed with in situ hybridization probes for DOG1, KIT, and PDGFRA. Other neoplasms in the differential diagnosis of GIST, including desmoid fibromatosis (0 of 17) and Schwannoma (0 of 3), were immunonegative for DOG1. Only 4 of 438 non-GIST cases were immunoreactive for DOG1. DOG1, a protein of unknown function, is expressed strongly on the cell surface of GISTs and is rarely expressed in other soft tissue tumors. Reactivity for DOG1 may aid in the diagnosis of GISTs, including PDGFRA mutants that fail to express KIT antigen, and lead to appropriate treatment with imatinib mesylate, an inhibitor of the KIT tyrosine kinase.


A modified sequential organ failure assessment score for critical care triage.
The Sequential Organ Failure Assessment (SOFA) score has been recommended for triage during a mass influx of critically ill patients, but it requires laboratory measurement of 4 parameters, which may be impractical with constrained resources. We hypothesized that a modified SOFA (MSOFA) score that requires only 1 laboratory measurement would predict patient outcome as effectively as the SOFA score. After a retrospective derivation in a prospective observational study in a 24-bed medical, surgical, and trauma intensive care unit, we determined serial SOFA and MSOFA scores on all patients admitted during the 2008 calendar year and compared the ability to predict mortality and the need for mechanical ventilation. A total of 1770 patients (56% male patients) with a 30-day mortality of 10.5% were included in the study. Day 1 SOFA and MSOFA scores performed equally well at predicting mortality with an area under the receiver operating curve (AUC) of 0.83 (95% confidence interval 0.81-.85) and 0.84 (95% confidence interval 0.82-.85), respectively (P = .33 for comparison). Day 3 SOFA and MSOFA predicted mortality for the 828 patients remaining in the intensive care unit with an AUC of 0.78 and 0.79, respectively. Day 5 scores performed less well at predicting mortality. Day 1 SOFA and MSOFA predicted the need for mechanical ventilation on day 3, with an AUC of 0.83 and 0.82, respectively. Mortality for the highest category of SOFA and MSOFA score (>11 points) was 53% and 58%, respectively. The MSOFA predicts mortality as well as the SOFA and is easier to implement in resource-constrained settings, but using either score as a triage tool would exclude many patients who would otherwise survive.


[Argentine psychiatric nosologies and nosographies].
Since the late 19th century, Argentinean psychiatrists have been developing classifcations of psychiatric disorders. Their work has had local originality and fruitful exchange with international controversies on the subject. The thinking of some Argentinean psychiatrists transcended the borders of the country and was adopted in the South American region, as was the case with the classifcation proposed by José T. Borda. There were also historical anticipations of concepts that were not known in other latitudes: "oligotimia", a category created by Enrique Pichon-Rivière, preceded the characterization of early childhood autism by Leo Kanner. In recent decades, Argentinean psychiatrists have adopted current international classifcations (DSM and CIE), but also actively participated in the elaboration of an original regional proposal: the Latin American Guide to Psychiatric Diagnosis (GLADP-VR 2012), and collaborated with the surveys carried out by the World Health Organization (WHO) for the revision of the future ICD 11. This article provides a detailed description of Argentinian classifcations, extensively quoting each author to provide a clear understanding of their thinking, as well as critical reviews of their proposals.


Effects of lipid-based nutrient supplements and infant and young child feeding counseling with or without improved water, sanitation, and hygiene (WASH) on anemia and micronutrient status: results from 2 cluster-randomized trials in Kenya and Bangladesh.
Anemia in young children is a global health problem. Risk factors include poor nutrient intake and poor water quality, sanitation, or hygiene. We evaluated the effects of water quality, sanitation, handwashing, and nutrition interventions on micronutrient status and anemia among children in rural Kenya and Bangladesh. We nested substudies within 2 cluster-randomized controlled trials enrolling pregnant women and following their children for 2 y. These substudies included 4 groups: water, sanitation, and handwashing (WSH); nutrition (N), including lipid-based nutrient supplements (LNSs; ages 6-24 mo) and infant and young child feeding (IYCF) counseling; WSH+N; and control. Hemoglobin and micronutrient biomarkers were measured after 2 y of intervention and compared between groups using generalized linear models with robust SEs. In Kenya, 699 children were assessed at a mean ± SD age of 22.1 ± 1.8 mo, and in Bangladesh 1470 participants were measured at a mean ± SD age of 28.0 ± 1.9 mo. The control group anemia prevalences were 48.8% in Kenya and 17.4% in Bangladesh. There was a lower prevalence of anemia in the 2 N intervention groups in both Kenya [N: 36.2%; prevalence ratio (PR): 0.74; 95% CI: 0.58, 0.94; WSH+N: 27.3%; PR: 0.56; 95% CI: 0.42, 0.75] and Bangladesh (N: 8.7%; PR: 0.50; 95% CI: 0.32, 0.78; WSH+N: 7.9%, PR: 0.46; 95% CI: 0.29, 0.73). In both trials, the 2 N groups also had significantly lower prevalences of iron deficiency, iron deficiency anemia, and low vitamin B-12 and, in Kenya, a lower prevalence of folate and vitamin A deficiencies. In Bangladesh, the WSH group had a lower prevalence of anemia (12.8%; PR: 0.74; 95% CI: 0.54, 1.00) than the control group, whereas in Kenya, the WSH+N group had a lower prevalence of anemia than did the N group (PR: 0.75; 95% CI: 0.53, 1.07), but this was not significant (P = 0.102). IYCF counseling with LNSs reduced the risks of anemia, iron deficiency, and low vitamin B-12. Effects on folate and vitamin A varied between studies. Improvements in WSH also reduced the risk of anemia in Bangladesh but did not provide added benefit over the nutrition-specific intervention. These trials were registered at clinicaltrials.gov as NCT01590095 (Bangladesh) and NCT01704105 (Kenya).


Emergency department companions of stroke patients: implications on quality of care.
Acute care of stroke victims largely relies on the rapid identification and timely clinical and radiological assessment. We evaluated the effect of the number of patient companions on the efficiency of the diagnostic process in the emergency department (ED).Consecutive stroke patients admitted to the ED between August 2011 and October 2012 were evaluated. Clinical, epidemiological, and timeline data (symptoms onset, ED arrival, computed tomography [CT] scanning, and recombinant tissue plasminogen activator infusion), as well as the number of accompanying persons in the ED were prospectively recorded. We used multivariate Poisson log linear models to analyze the association of number of companions adjusted and door-to-CT times and logistic regression for the analysis of the successful identification of stroke patient by ED triage nurse.Out of a total of 724 stroke patients admitted, data regarding number of ED companions were available for 610 (84.3%) patients. Number of companions was associated with higher National Institute of Health Stroke Scale and speech disturbances. It was found to be independently associated with shorter time to CT scanning adjusted for the stroke severity, sex, and speech disturbances (no companions as a reference group, relative risks 0.82, 0.73, and 0.70 for 1, 2, and ≥3 companions, respectively, all P < 0.001). Similarly, number of companions was associated with higher rates of stroke recognition by the triage nurse adjusted for covariates (odds ratios 2.11, 2.62, and 4.11, respectively, all P < 0.05).Our findings suggest that the family members and other companions could serve as facilitators of faster and more effective ED management of stroke patients, possibly improving their outcome.


Ferroptosis induced by the biocontrol agent Pythium oligandrum enhances soybean resistance to Phytophthora sojae.
Ferroptosis is a newly discovered form of cell death accompanied by iron accumulation and lipid peroxidation. Both biotic and abiotic stresses can induce ferroptosis in plant cells. In the case of plant interactions with pathogenic Phytophthora oomycetes, the roles of ferroptosis are still largely unknown. Here, we performed transcriptome analysis on soybean plants treated with the biocontrol agent Pythium oligandrum, a soilborne and non-pathogenic oomycete capable of inducing plant resistance against Phytophthora sojae infection. Expression of homologous soybean genes involved in ferroptosis and resistance was reprogrammed upon P. oligandrum treatment. Typical hallmarks for characterizing ferroptosis were detected in soybean hypocotyl cells, including decreased glutathione (GSH) level, accumulation of ferric ions, and lipid peroxidation by reactive oxygen species (ROS). Meanwhile, ferroptosis-like cell death was triggered by P. oligandrum to suppress P. sojae infection in soybean. Protection provided by P. oligandrum could be attenuated by the ferroptosis inhibitor ferrostatin-1 (Fer-1), suggesting the critical role of ferroptosis in soybean resistance against P. sojae. Taken together, these results demonstrate that ferroptosis is a P. oligandrum-inducible defence mechanism against oomycete infection in soybean.


Acetabular posterior wall fracture. 38 cases followed for 5 years.
Thirty-eight patients with a fracture of the posterior wall of the acetabulum were reviewed after 5 (2-12) years. Of 18 patients with successful manual reduction of a femoral head dislocation, a small fracture fragment, no sciatic nerve injury and who were not operated on, 17 had a good result. Of 20 patients who were operated on either because of the large size of the fracture fragment or because of a persistent dislocation of the femoral head, 6 had a poor result due to femoral head necrosis. In these 6 patients the reduction had been delayed and the acetabular osteochondral lesion was more severe than in the other patients. Skeletal traction seems unnecessary in the treatment of acetabular posterior wall fracture.


The Mediterranean: the cradle of Anthoxanthum (Poaceae) diploid diversity.
Knowledge of diploid phylogeny and ecogeography provide a foundation for understanding plant evolutionary history, diversification patterns and taxonomy. The genus Anthoxanthum (vernal grasses, Poaceae) represents a taxonomically intricate polyploid complex with large phenotypic variation and poorly resolved evolutionary relationships. The aims of the study were to reveal: (1) evolutionary lineages of the diploid taxa and their genetic differentiation; (2) the past distribution of the rediscovered 'Mediterranean diploid'; and (3) possible migration routes of diploids in the Mediterranean. A combined approach involving sequencing of two plastid regions ( trnL-trnF and rpl32-trnL ), nrDNA ITS, rDNA FISH analyses, climatic niche characterization and spatio-temporal modelling was used. Among the examined diploid species, only two well-differentiated evolutionary lineages were recognized: Anthoxanthum gracile and A. alpinum . The other taxa - A. aristatum, A. ovatum, A. maderense and the 'Mediterranean diploid' - form a rather intermixed group based on the examined molecular data. In situ rDNA localization enabled identification of the ancestral Anthoxanthum karyotype, shared by A. gracile and two taxa from the crown group. For the studied taxa, ancestral location probabilities for six discrete geographical regions in the Mediterranean were proposed and likely scenarios of gradual expansion from them were suggested. Modelling past and present distributions shows that the 'Mediterranean diploid' has already been occurring in the same localities for 120 000 years. Highly congruent results were obtained and dated the origin and first diversification of Anthoxanthum to the Miocene. The later divergence probably took place in the Pleistocene and started polyploid evolution within the genus. The most recent diversification event is still occurring, and incomplete lineage sorting prevents full diversification of taxa at the molecular level, despite clear separation based on climatic niches. The 'Mediterranean diploid' is hypothesized to be a possible relic of the most recent common ancestor of Anthoxanthum due to their sharing of ancestral features.


Bayesian estimation of differential transcript usage from RNA-seq data.
Next generation sequencing allows the identification of genes consisting of differentially expressed transcripts, a term which usually refers to changes in the overall expression level. A specific type of differential expression is differential transcript usage (DTU) and targets changes in the relative within gene expression of a transcript. The contribution of this paper is to: (a) extend the use of cjBitSeq to the DTU context, a previously introduced Bayesian model which is originally designed for identifying changes in overall expression levels and (b) propose a Bayesian version of DRIMSeq, a frequentist model for inferring DTU. cjBitSeq is a read based model and performs fully Bayesian inference by MCMC sampling on the space of latent state of each transcript per gene. BayesDRIMSeq is a count based model and estimates the Bayes Factor of a DTU model against a null model using Laplace's approximation. The proposed models are benchmarked against the existing ones using a recent independent simulation study as well as a real RNA-seq dataset. Our results suggest that the Bayesian methods exhibit similar performance with DRIMSeq in terms of precision/recall but offer better calibration of False Discovery Rate.


On the formation of equilibrium gels via a macroscopic bond limitation.
Restricting the number of attractive physical "bonds" that can form between particles in a fluid suppresses the usual demixing phase transition to very low particle concentrations, allowing for the formation of open, percolated, and homogeneous states, aptly called equilibrium or "empty" gels. Most demonstrations of this concept have directly limited the microscopic particle valence via anisotropic (patchy) attractions; however, an alternative macroscopic valence limitation would be desirable for greater experimental tunability and responsiveness. One possibility, explored in this paper, is to employ primary particles with attractions mediated via a secondary species of linking particles. In such a system, the linker-to-primary particle ratio serves as a macroscopic control parameter for the average microscopic valence. We show that the phase behavior of such a system predicted by Wertheim's first order perturbation theory is consistent with equilibrium gel formation: the primary particle concentrations corresponding to the two-phase demixing transition are significantly suppressed at both low and high linker-to-primary particle ratios. Extensive molecular dynamics simulations validate these theoretical predictions but also reveal the presence of loops of bonded particles, which are neglected in the theory. Such loops cause densification and inhibit percolation, and hence the range of viable empty gel state conditions is somewhat reduced relative to the Wertheim theory predictions.


Modulation of Singlet-Triplet Gap in Atomically Precise Silver Cluster-Assembled Material.
Silver cluster-based solids have garnered considerable attention owing to their tunable luminescence behavior. While surface modification has enabled the construction of stable silver clusters, controlling interactions among clusters at the molecular level has been challenging due to their tendency to aggregate. Judicious choice of stabilizing ligands becomes pivotal in crafting a desired assembly. However, detailed photophysical behavior as a function of their cluster packing remained unexplored. Here, we modulate the packing pattern of Ag12 clusters by varying the nitrogen-based ligand. CAM-1 formed through coordination of the tritopic linker molecule and NC-1 with monodentate pyridine ligand; established via non-covalent interactions. Both the assemblies show ligand-to-metal-metal charge transfer (LMMCT) based cluster-centered emission band(s). Temperature-dependent photoluminescence spectra exhibit blue shifts at higher temperatures, which is attributed to the extent of the thermal reverse population of the S1 state from the closely spaced T1 state. The difference in the energy gap (ΔEST) dictated by their assemblies played a pivotal role in the way that Ag12 cluster assembly in CAM-1 manifests a wider ΔEST and thus requires higher temperatures for reverse intersystem crossing (RISC) than assembly of NC-1. Such assembly-defined photoluminescence properties underscore the potential toolkit to design new cluster- assemblies with tailored optoelectronic properties.


Developmental Psychopathology Courts Developmental Neurobiology: Current Issues and Future Challenges.
The last decade has witnessed significant advances in theory and research in the fields of developmental psychopathology and developmental neurobiology. These two fields have much in common, sharing a number of guiding principles and assumptions. This article describes the research implications that these shared principles contain for the growing partnership between developmental psychopathology and developmental neurobiology. Based upon the methods successfully employed in the developmental neurosciences, the author emphasizes that developmental psychopathology must (A) construct more specific (even clever) research questions, (B) develop research tools more capable of examining time-dependent brain-behavior relations, (C) outline and test particular causal mechanisms and their contextual dependencies, and (D) avoid formulaic, nonthinking statistics and design methods that often characterize mental health research.


A Role for Superficial Heat Therapy in the Management of Non-Specific, Mild-to-Moderate Low Back Pain in Current Clinical Practice: A Narrative Review.
Low back pain (LBP) is a leading cause of disability. It significantly impacts the patient's quality of life, limits their daily living activities, and reduces their work productivity. To reduce the burden of LBP, several pharmacological and non-pharmacological treatment options are available. This review summarizes the role of superficial heat therapy in the management of non-specific mild-to-moderate LBP. First, we outline the common causes of LBP, then discuss the general mechanisms of heat therapy on (LBP), and finally review the published evidence regarding the impact of superficial heat therapy in patients with acute or chronic non-specific LBP. This review demonstrates that continuous, low-level heat therapy provides pain relief, improves muscular strength, and increases flexibility. Therefore, this effective, safe, easy-to-use, and cost-effective non-pharmacological pain relief option is relevant for the management of non-specific mild or moderate low back pain in current clinical practice.


[Trends in the use of primary radiotherapy for cancer in the Netherlands in patients with breast, prostate, rectal and lung tumours].
To provide insight in the application of radiotherapy as part of primary treatment of patients with cancer in the Netherlands. Retrospective, descriptive population-based study. Data concerning patients with breast, prostate, rectal and non-small cell lung cancer were selected from the Netherlands Cancer Registry in 4 regions, covering 50% of the Dutch population. The selection concerned data from 1997-2008 and, except for prostate cancer, only patients without distant metastases were included. Between 1997 and 2008, the use of primary external radiotherapy increased approximately 7% in breast cancer patients and approximately 30% in rectal cancer patients. In the latter group preoperative radiotherapy strongly increased, while postoperative radiotherapy decreased. For prostate cancer there was an increase in brachytherapy (9%). The use of external beam radiotherapy in patients with prostate cancer and non-small cell lung cancer remained the same. Regional differences in the extent of use of radiotherapy for breast and rectal cancer clearly decreased. These differences remained limited for external beam radiotherapy in prostate and non-small cell lung cancer. Older patients less often received radiotherapy. The increase in use of radiotherapy for breast cancer is explained by the increase in breast conserving surgery. The trends in use in patients with rectal cancer and breast cancer are presumably related to the implementation of multidisciplinary practice guidelines. The implementation of these guidelines probably also contributed to the decrease in regional differences in the use of radiotherapy.


Expression and genomic integration of transgenes after Agrobacterium-mediated transformation of mature barley embryos.
Mature embryos in tissue cultures are advantageous because of their abundance and rapid germination, which reduces genomic instability problems. In this study, 2-day-old isolated mature barley embryos were infected with 2 Agrobacterium hypervirulent strains (AGL1 and EHA105), followed by a 3-day period of co-cultivation in the presence of L-cystein amino acid. Chimeric expression of the b-glucuronidase gene (gusA) directed by a viral promoter of strawberry vein banding virus was observed in coleoptile epidermal cells and seminal roots in 5-day-old germinated seedlings. In addition to varying infectivity patterns in different strains, there was a higher ratio of transient b-glucuronidase expression in developing coleoptiles than in embryonic roots, indicating the high competency of shoot apical meristem cells in the mature embryo. A total of 548 explants were transformed and 156 plants developed to maturity on G418 media after 18-25 days. We detected transgenes in 74% of the screened plant leaves by polymerase chain reaction, and 49% of these expressed neomycin phosphotransferase II gene following AGL1 transformation. Ten randomly selected T0 transformants were analyzed using thermal asymmetric interlaced polymerase chain reaction and 24 fragments ranged between 200-600 base pairs were sequenced. Three of the sequences flanked with transferred-DNA showed high similarity to coding regions of the barley genome, including alpha tubulin5, homeobox 1, and mitochondrial 16S genes. We observed 70-200-base pair filler sequences only in the coding regions of barley in this study.


Diffraction effects detection for HDR image-based measurements.
Modern imaging techniques have proved to be very efficient to recover a scene with high dynamic range (HDR) values. However, this high dynamic range can introduce star-burst patterns around highlights arising from the diffraction of the camera aperture. The spatial extent of this effect can be very wide and alters pixels values, which, in a measurement context, are not reliable anymore. To address this problem, we introduce a novel algorithm that, utilizing a closed-form PSF, predicts where the diffraction will affect the pixels of an HDR image, making it possible to discard them from the measurement. Our approach gives better results than common deconvolution techniques and the uncertainty values (convolution kernel and noise) of the algorithm output are recovered.


Fibroblast activation protein drives tumor metastasis via a protease-independent role in invadopodia stabilization.
During metastasis, tumor cells invade through the basement membrane and intravasate into blood vessels and then extravasate into distant organs to establish metastases. Here, we report a critical role of a transmembrane serine protease fibroblast activation protein (FAP) in tumor metastasis. Expression of FAP and TWIST1, a metastasis driver, is significantly correlated in several types of human carcinomas, and FAP is required for TWIST1-induced breast cancer metastasis to the lung. Mechanistically, FAP is localized at invadopodia and required for invadopodia-mediated extracellular matrix degradation independent of its proteolytic activity. Live cell imaging shows that association of invadopodia precursors with FAP at the cell membrane promotes the stabilization and growth of invadopodia precursors into mature invadopodia. Together, our study identified FAP as a functional target of TWIST1 in driving tumor metastasis via promoting invadopodia-mediated matrix degradation and uncovered a proteolytic activity-independent role of FAP in stabilizing invadopodia precursors for maturation.


Silent Tumefactive Demyelinating Lesions and Radiologically Isolated Syndrome.
Demyelinating lesions larger than 2 cm in diameter, with or without edema, are known as tumefactive demyelinating lesions (TDLs). They constitute a rare inflammatory demyelinating disorder of the central nervous system. TDLs are typically characterized by headaches, cortical symptoms such as aphasia, hemiparesis, hemisensory deficits, seizures, and changes in consciousness. TDLs may occur in patients with or without an established diagnosis of MS or may occur as the initial demyelinating event. They may also be observed during follow-up in patients with MS, neuromyelitis optica, acute disseminated encephalomyelitis, or other autoimmune diseases. Differential diagnosis includes brain tumors, abscess, granulomatous diseases, and vasculitis. In some cases, it may be very difficult to distinguish TDLs from a tumor, such that biopsy might be needed. However, no cases of asymptomatic TDLs have yet been reported in the literature. Hence, in this report, we present a case involving an asymptomatic TDL detected incidentally during magnetic resonance imaging in an 18-year-old man. The patient did not develop any symptoms during the 1-year follow-up period. During follow-up, the patient was diagnosed with a radiologically isolated syndrome. TDLs have not previously been identified as radiologically isolated syndrome. Thus, reporting similar cases in the future will help in further understanding this phenomenon.


Value of routine follow up of women treated for early carcinoma of the breast.
The value of routine follow up of women treated for early breast cancer by mastectomy with or without postoperative radiotherapy was assessed retrospectively. Over eight years 546 patients made 6863 clinic visits, during which 192 first relapses were detected. Ninety three relapses were detected at scheduled (routine) visits and 99 at unscheduled (interval) visits. First relapses within the treated area or in the contralateral breast were detected significantly more commonly at routine visits than were first metastatic relapses (66/89 (74%) compared with 27/103 (26%)). Patients whose local relapse was detected at a routine visit had a significantly better survival than those whose local relapse was detected at an interval visit. A relapse that was potentially curable (local or in the contralateral breast) was detected at 66 (1%) of 6764 routine visits, but only 26 (39%) of these patients remained free of disease. It is concluded that the intensity of follow up of such patients could be reduced without any adverse effect on prognosis but with appreciable financial and other benefits.


Treatment, trial participation and survival in adult acute myeloid leukemia: a population-based study in the Netherlands, 1989-2012.
Large, comprehensive population-based studies in acute myeloid leukemia (AML) are scarce. We conducted a nationwide population-based study on treatment, trial participation and survival among all adult patients diagnosed with AML (n=12,032) and acute promyelocytic leukemia (APL; n=585) in the Netherlands between 1989-2012. Patients were categorized into four periods and four age groups (18-40, 41-60, 61-70 and >70 years). The application of allogeneic stem cell transplantation increased over time among AML patients up to age 70 years. For APL patients, the use of chemotherapy increased across all age groups. When a clinical trial was open for accrual in the Netherlands, the inclusion rates were 68%, 57%, 30% and 12% for AML patients in the four age groups, respectively (data for APL unavailable). Relative survival improved over time among AML (up to age 70 years) and APL patients. In the period 2007-2012, 5-year relative survival rates were 54%, 38%, 14% and 2% for AML patients and 84%, 75%, 54% and 37% for APL patients in the four age groups, respectively. As survival remained poor for older AML patients over the last two decades, clinical trials and active participation in those trials, are warranted that explore innovative treatment strategies for this elderly population.


Evaluation of two-fold fully conditional specification multiple imputation for longitudinal electronic health record data.
Most implementations of multiple imputation (MI) of missing data are designed for simple rectangular data structures ignoring temporal ordering of data. Therefore, when applying MI to longitudinal data with intermittent patterns of missing data, some alternative strategies must be considered. One approach is to divide data into time blocks and implement MI independently at each block. An alternative approach is to include all time blocks in the same MI model. With increasing numbers of time blocks, this approach is likely to break down because of co-linearity and over-fitting. The new two-fold fully conditional specification (FCS) MI algorithm addresses these issues, by only conditioning on measurements, which are local in time. We describe and report the results of a novel simulation study to critically evaluate the two-fold FCS algorithm and its suitability for imputation of longitudinal electronic health records. After generating a full data set, approximately 70% of selected continuous and categorical variables were made missing completely at random in each of ten time blocks. Subsequently, we applied a simple time-to-event model. We compared efficiency of estimated coefficients from a complete records analysis, MI of data in the baseline time block and the two-fold FCS algorithm. The results show that the two-fold FCS algorithm maximises the use of data available, with the gain relative to baseline MI depending on the strength of correlations within and between variables. Using this approach also increases plausibility of the missing at random assumption by using repeated measures over time of variables whose baseline values may be missing.


Objective vs. Self-report Sedentary Behavior in Overweight and Obese Young Adults.
Sedentary behavior (SED) has been measured almost exclusively by self-reported total SED or television time in longitudinal studies. This manuscript aimed to compare self-reported vs. objectively measured SED. Among overweight and obese young adults enrolled in a weight loss trial, baseline SED was assessed by 3 methods: 1) a questionnaire assessing 8 common SEDs (SEDQ), 2) 1 question assessing SED from the Global Physical Activity Questionnaire (SEDGPAQ), and 3) a monitor worn on the arm (SEDOBJ). In addition, television time (SEDTV) was isolated from the SEDQ. SED measures were compared using Spearman's correlations, signed-rank tests, and Bland-Altman plots. In 448 participants, SEDQ and SEDGPAQ were only weakly associated with SEDOBJ (rs = 0.21; P < .001, rs = 0.32; P < .001, respectively). Compared with SEDOBJ, SEDQ more often overestimated SEDOBJ (median difference: 1.1 hours/day; P < .001), while SEDGPAQ more often underestimated SEDOBJ (median difference: -0.7 hours/day; P < .001). The correlation between SEDTV and SEDOBJ was not significantly different from 0 (rs = 0.08; P = .08). SEDQ and SEDGPAQ were weakly correlated with, and significantly different from, SEDOBJ in overweight and obese young adults. SEDTV was not related to SEDOBJ. The poor associations of self-reported and objectively measured SED could affect interpretation and comparison across studies relating SED to adverse health outcomes.


Lymphatic vascular response to acute inflammation.
During acute inflammation, functioning lymphatics are believed to reduce edema and to provide a transiting route for immune cells, but the extent at which the dermal lymphatic remodeling impacts lymphatic transport or the factors regulating these changes remains unclear. Herein we quantify the increase in lymphatic endothelial cells (LECs) and examine the expression of pro-angiogenenic and lymphangiogenic factors during acute cutaneous hypersensitivity (CHS). We found that LECs actively proliferate during CHS but that this proliferation does not affect the lymphatic vessel density. Instead, lymphatic remodeling is accompanied by lymphatic vessel leakiness and lower ejection of lymph fluid, which is observed only in the proximal lymphatic vessel draining the inflamed area. LECs and the immune cells release growth factors and cytokines during inflammation, which impact the lymphatic microenvironment and function. We identified that FGF-2, PLGF-2, HGF, EGF, and KC/CXCL17 are differentially expressed within tissues during acute CHS, but both VEGF-C and VEGF-D levels do not significantly change. Our results indicate that VEGF-C and VEGF-D are not the only players and other factors may be responsible for the LECs proliferation and altered lymphatic function in acute CHS.


Hyperaldosteronism after decreased renal K+ excretion in KCNMB2 knockout mice.
The kidney is the primary organ ensuring K(+) homeostasis. K(+) is secreted into the urine in the distal tubule by two mechanisms: by the renal outer medullary K(+) channel (Kir1.1) and by the Ca(2+)-activated K(+) channel (KCa1.1). Here, we report a novel knockout mouse of the β2-subunit of the KCa1.1 channel (KCNMB2), which displays hyperaldosteronism after decreased renal K(+) excretion. KCNMB2(-/-) mice displayed hyperaldosteronism, normal plasma K(+) concentration, and produced dilute urine with decreased K(+) concentration. The normokalemia indicated that hyperaldosteronism did not result from primary aldosteronism. Activation of the renin-angiotensin-aldosterone system was also ruled out as renal renin mRNA expression was reduced in KCNMB2(-/-) mice. Renal K(+) excretion rates were similar in the two genotypes; however, KCNMB2(-/-) mice required elevated plasma aldosterone to achieve K(+) balance. Blockade of the mineralocorticoid receptor with eplerenone triggered mild hyperkalemia and unmasked reduced renal K(+) excretion in KCNMB2(-/-) mice. Knockout mice for the α-subunit of the KCa1.1 channel (KCNMA1(-/-) mice) have hyperaldosteronism, are hypertensive, and lack flow-induced K(+) secretion. KCNMB2(-/-) mice share the phenotypic traits of normokalemia and hyperaldosteronism with KCNMA1(-/-) mice but were normotensive and displayed intact flow-induced K(+) secretion. Despite elevated plasma aldosterone, KNCMB2(-/-) mice did not display salt-sensitive hypertension and were able to decrease plasma aldosterone on a high-Na(+) diet, although plasma aldosterone remained elevated in KCNMB2(-/-) mice. In summary, KCNMB2(-/-) mice have a reduced ability to excrete K(+) into the urine but achieve K(+) balance through an aldosterone-mediated, β2-independent mechanism. The phenotype of KCNMB2 mice was similar but milder than the phenotype of KCNMA1(-/-) mice.


Physical activity at the government-recommended level and obesity-related health outcomes: a longitudinal study (Early Bird 37).
In the UK and USA, government guidelines for childhood physical activity have been set (> or =60 min/day at > or =3 metabolic equivalents of thermogenesis (METs)), and body mass index (BMI) chosen as the outcome measure. To determine the extent to which physical activity at the government-recommended intensity is associated with change in body mass/fat and metabolic health in pre-pubertal children. Non-intervention longitudinal study of 113 boys and 99 girls (born 1995/96) recruited from 54 schools. Physical activity (Actigraph accelerometers), changes in body mass (raw and age/gender-standardised BMI), fatness (skin-fold thickness and waist circumference) and metabolic status (insulin resistance, triglycerides, cholesterol/HDL ratio and blood pressure - separately and as a composite metabolic z score) were measured on four annual occasions (5, 6, 7 and 8 years). Mean physical activity did not change over time in either sex. Averaging the 7-day recordings from four time points rather than one increased the reliability of characterising a child's activity from 71% to 90%. Some 42% of boys and 11% of girls met the guideline. There were no associations between physical activity and changes in any measurement of body mass or fatness over time in either sex (eg, BMI standard deviation scores: r = -0.02, p = 0.76). However, there was a small to moderate inverse association between physical activity and change in composite metabolic score (r = -0.19, p<0.01). Mixed effects modelling showed that the improvement in metabolic score among the more active compared to the less active children was linear with time (-0.08 z scores/year, p = 0.001). In children, physical activity above the government-recommended intensity of 3 METs is associated with a progressive improvement in metabolic health but not with a change in BMI or fatness. Girls habitually undertake less physical activity than boys, questioning whether girls in particular should be encouraged to do more, or the recommendations adjusted for girls.


Hypercapnic and Hypoxic Respiratory Response During Wakefulness and Sleep in a Streptozotocin Model of Alzheimer's Disease in Rats.
Besides the typical cognitive decline, patients with Alzheimer's disease (AD) develop disorders of the respiratory system, such as sleep apnea, shortness of breath, and arrhythmias. These symptoms are aggravated with the progression of the disease. However, the cause and nature of these disturbances are not well understood. Here, we treated animals with intracerebroventricular streptozotocin (STZ, 2 mg/kg), a drug that has been described to cause Alzheimer-like behavioral and histopathological impairments. We measured ventilation (V̇E), electroencephalography, and electromyography during normocapnia, hypercapnia, and hypoxia in Wistar rats. In addition, we performed western blot analyses for phosphorylated tau, total tau, and amyloid-β (Aβ) peptide in the locus coeruleus (LC), retrotrapezoid nucleus, medullary raphe, pre-Bötzinger/Bötzinger complex, and hippocampus, and evaluated memory and learning acquisition using the Barnes maze. STZ treatment promoted memory and learning deficits and increased the percentage of total wakefulness during normocapnia and hypercapnia due to a reduction in the length of episodes of wakefulness. CO2-drive to breathe during wakefulness was increased by 26% in STZ-treated rats due to an enhanced tidal volume, but no changes in V̇E were observed in room air or hypoxic conditions. The STZ group also showed a 70% increase of Aβ in the LC and no change in tau protein phosphorylation. In addition, no alteration in body temperature was observed. Our findings suggest that AD animals present an increased sensitivity to CO2 during wakefulness, enhanced Aβ in the LC, and sleep disruption.


Internet conferences in glycobiology.
In this article we describe recent activities in the use of electronic conferencing in glycobiology focusing on our experiences with the organization and development of the Second Electronic Glycoscience Conference (EGC-2), which was held on the Internet and World Wide Web in September 1996. EGC-2 involved the presentation and discussion of scientific research results in a virtual conferencing environment which incorporated virtual replicas of many activities usually observed at a physical conference in addition to features unique to the electronic medium. Highlights of the scientific program and technical developments in the design and use of these facilities are briefly described. EGC-3 will be held in October 1997.


Ilio-Sacral (IS) Screw Fixation for Sacral and Sacroiliac Joint (SIJ) Injuries in Children.
Treatment of sacral fractures and sacroiliac joint (SIJ) disruption with percutaneous ilio-sacral (IS) screw fixation had become a more popular treatment option. There has been no study that specifically assessed IS fixation in children. The purpose of this study is present our results with fixation of the sacral fractures and SIJ disruption using IS screw in children 18 years old and younger. This is a retrospective review chart for children with sacral fracture or SIJ disruption who were treated by IS fixation in the period from 2000 to 2012. The patients were assessed for the following (age, sex, type of injury, associated injuries, surgery, complications, postoperative return of function, healing of the injury, and return to function). In the studied period (2000 to 2012), 11 patients who had either sacral fracture (4 patients) or SIJ (7 patients) disruption were treated by IS screws. The average age of these patients was 14 years (range, 6 to 17 y). Six patients had 1 screw and 5 patients had 2 screws. Eight patients had their entire fixation in S1, and 3 patients had 1 screw in S1 and 1 screw in S2. All screws were cannulated and were inserted over a guidewire with fluoroscopy and/or navigation guidance. Five patients had added anterior fixation of the pelvis. One patient was lost for follow-up. All patients (except 1) achieved healing of their injuries with no displacement or implant failure with return of function. One patient had failure of fixation and needed revision. One patient had neurological complication related to screw insertion. IS screws can be safely used to treat sacral fractures and SIJ injuries in children. This was feasible in children as young as 6 years old. The complications of the procedure were minimal with good stability obtained by IS screws.


Rupture of zwitterionic lipid vesicles by an amphipathic, α-helical peptide: indirect effects of sensor surface and implications for experimental analysis.
Surface-based measurement approaches offer competitive advantages for studying lipid membranes and membrane-active drug candidates. Continued development of surface-based membrane assays for pharmaceutical and biotechnology applications should account for physicochemical properties of the sensor surface. As a model system, the rupture of surface-adsorbed, zwitterionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid vesicles by an amphipathic, α-helical (AH) peptide, which attaches to the vesicle surface and destabilizes the membrane, was investigated herein. The kinetics of vesicle rupture on three different sensor surfaces (gold, titanium oxide, and aluminum oxide) were tracked by simultaneous quartz crystal microbalance-dissipation (QCM-D) and ellipsometry. On all three surfaces, complete vesicle rupture was observed. However, the corresponding kinetics of the vesicle rupture process and its sub-steps varied significantly between the three surfaces. In particular, the experimental data supports that the vesicle-substrate interaction influences the rupture process via differences in vesicle shape and lipid-substrate adhesion.


Primary care in the emergency room: a collaborative model.
Emergency rooms have become primary care centers for a large portion of the population. Unfortunately, most are neither designed nor appropriately staffed to deliver first-line, continuous, comprehensive, family-oriented, and self-actualizing care. This paper describes a nurse-managed collaborative primary care practice model that has been functioning for 8 years in an inner city emergency department.


Quantification of chronic functional mitral regurgitation by automated 3-dimensional peak and integrated proximal isovelocity surface area and stroke volume techniques using real-time 3-dimensional volume color Doppler echocardiography: in vitro and clinical validation.
The aim of this study was to test the accuracy of an automated 3-dimensional (3D) proximal isovelocity surface area (PISA) (in vitro and patients) and stroke volume technique (patients) to assess mitral regurgitation (MR) severity using real-time volume color flow Doppler transthoracic echocardiography. Using an in vitro model of MR, the effective regurgitant orifice area and regurgitant volume (RVol) were measured by the PISA technique using 2-dimensional (2D) and 3D (automated true 3D PISA) transthoracic echocardiography. The mean anatomic regurgitant orifice area (0.35±0.10 cm(2)) was underestimated to a greater degree by the 2D (0.12±0.05 cm(2)) than the 3D method (0.25±0.10 cm(2); P<0.001 for both). Compared with the flowmeter (40±14 mL), the RVol by 2D PISA (20±19 mL) was underestimated (P<0.001), but the 3D peak (43±16 mL) and integrated PISA-based (38±14 mL) RVol were comparable (P>0.05 for both). In patients (n=30, functional MR), 3D effective regurgitant orifice area correlated well with cardiac magnetic resonance imaging RVol r=0.84 and regurgitant fraction r=0.80. Compared with cardiac magnetic resonance imaging RVol (33±22 mL), the integrated PISA RVol (34±26 mL; P=0.42) was not significantly different; however, the peak PISA RVol was higher (48±27 mL; P<0.001). In addition, RVol calculated as the difference in automated mitral and aortic stroke volumes by real-time 3D volume color flow Doppler echocardiography was not significantly different from cardiac magnetic resonance imaging (34±21 versus 33±22 mL; P=0.33). Automated real-time 3D volume color flow Doppler based 3D PISA is more accurate than the 2D PISA method to quantify MR. In patients with functional MR, the 3D RVol by integrated PISA is more accurate than a peak PISA technique. Automated 3D stroke volume measurement can also be used as an adjunctive method to quantify MR severity.


Pattern selection when a layer buckles on a soft substrate.
If a neo-Hookean elastic layer adhered to a neo-Hookean substrate grows equibiaxially, it will buckle into a topographic pattern. Here, we combine higher order perturbation theory and finite element numerics to predict the pattern formed just beyond the buckling threshold. More precisely, we construct a series of solutions corresponding to hexagonal, square and stripe patterns, and expand the elastic energy for each pattern as a Landau-like energy series in the topography amplitude. We see that, for square and stripe patterns, the elastic energy is invariant under topography inversion, making the instabilities supercritical. However, since patterns of hexagonal dents are physically different to patterns of hexagonal bumps, the hexagonal energy lacks this invariance. This lack introduces a cubic term which causes hexagonal patterns to be formed subcritically and are hence energetically favoured. Our analytic calculation of the cubic term allows us to determine that dents are favoured in incompressible systems, but bumps are favored in sufficiently compressible systems. Finally, we consider a stiff layer sandwiched between an identical substrate and superstrate pair. This system has topography inversion symmetry, so hexagons form supercritically, and square patterns are favoured. We use finite element calculations to verify our theoretical predictions for each pattern, and confirm which pattern is selected. Previous work has used a simplified elastic model (a plate & a linear elastic substrate) that possesses invariance under topography inversion, and hence incorrectly predicted square patterns. Our work demonstrates that large strain geometry is sufficient to break this symmetry and explain the hexagonal dent patterns observed in buckling experiments.